Pyrimidine derivatives for the treatment of bacterial diseases

ABSTRACT

The present invention relates to novel compounds of formula I: 
                         
or a pharmaceutically acceptable salt thereof, wherein the integers are as defined in the description.
 
     The claimed compounds are useful for the treatment of a bacterial infection. Also claimed is a composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of the claimed compounds, the use of the claimed compounds or compositions for the manufacture of a medicament for the treatment of a bacterial infection and a process for preparing the claimed compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority of the benefits of the filing ofApplication Nos. EP 12166140.9 filed Apr. 30, 2012, andPCT/EP2013/058980 (WO2013/164337 A9) filed Apr. 30, 2013. The completedisclosures of the aforementioned related patent applications are herebyincorporated herein by reference for all purposes.

The present invention relates to compounds useful for the treatment of abacterial disease, in particular diseases caused by a certainnon-mycobacterium, Staphylococcus aureus. The compounds may be useful inany mammal (e.g. human or animal). The invention also relates to novelcompounds, compositions, processes and uses.

BACKGROUND OF THE INVENTION

Bacterial infections are prevalent in the world and there is a high needfor compounds that treat bacterial infections. There are several knowntypes/strains of bacteria that exist and it is a particular goal in themedical field to find compounds that are selectively active againstcertain types/strains of bacteria.

There are already several drugs known that have activity againstnon-mycobacteria, but there remains a need for such compounds,particularly because bacteria can gain resistance to certaincompounds/drugs. Compounds that have selective activity against certaintypes/strains of bacteria will clearly be advantageous, for instancethese compounds may have the advantage that the bacteria cannot build upresistance to other strains of bacteria.

Indeed, the purpose of the present invention is to provide compoundsthat have selective activity against a particular non-mycobacterium,specifically Staphylococcus aureus.

Certain pyrimidine compounds are publically available or have beendisclosed via Chemical Abstracts Service, but such compounds have nothad any particular use ascribed to them. International patentapplication WO 2005/070899 and US patent application US 2005/182073 bothdisclose certain pyrimidines that may be useful for controlling harmfulorganisms (for instance organisms that attack plants). Internationalpatent application WO 2003/077656 discloses certain pyrimidines that maybe useful as antibacterials. These documents only disclose certain typesof pyrimidines.

US patent U.S. Pat. No. 6,887,870 B1 discloses various compounds assodium/proton exchange inhibitors, but does not disclose such compoundsfor use in the treatment of bacterial infections. International patentapplications WO 2011/073378, WO 2011/060976 and WO 2011/061214apparently disclose certain compounds for use as antibacterials, butthese documents only disclose a limited range of compounds.

SUMMARY OF THE INVENTION

There is provided a compound of formula I for use asmedicament/pharmaceutical, wherein formula I represents:

wherein:Y represents:

(ii) —CF₃;(iii) —N(C₁₋₆ alkyl)₂ (e.g. —N(CH₃)₂); or(iv) C₃₋₆ cycloalkyl (e.g. cyclopropyl);N^(v), N^(w), N^(x), N^(y) and N^(z) independently represent —N═ or—C(H)═ (or —C(A⁴)=) but wherein only a maximum of three of N^(v), N^(w),N^(x), N^(y) and N^(z) may represent —N═;n represents 0, 1 or 2 (but preferably represents 0);X¹ and X² independently represent —N— or —C(H)—;when X¹ represents —N—, Q¹ represents a direct bond, —C(O)— or —S(O)₂—;when X¹ represents —C(H)—, Q¹ represents a direct bond or —N(R^(z))—;R^(z) represents hydrogen or C₁₋₆ alkyl;R^(x) represents C₁₋₆ alkyl (optionally substituted by one or moresubstituents selected from ═O and A¹), aryl or heteroaryl (which lattertwo groups are each optionally substituted by one or more substituentsselected from A² and A³, respectively);R^(y), R^(y1) and R^(y2) independently represent hydrogen, halo, —CN,—OR¹⁰, —N(R¹¹)(R¹²) or C₁₋₆ alkyl (optionally substituted by one or morehalo (e.g. fluoro) atoms);A¹, A², A³ and A⁴ independently represent halo, —CN, —OR¹,—S(O)₀₋₂C₁₋₃alkyl, C₁₋₆ alkyl (optionally substituted by one or morehalo substituents), heterocyloalkyl (optionally substituted by one ormore substituents selected from C₁₋₃ alkyl and halo), aryl or heteroaryl(which latter two groups are optionally substituted by one or moresubstituents selected from B¹ and B², respectively);each R¹ and R¹⁰ independently represent hydrogen, C₁₋₆ alkyl (optionallysubstituted by one or more halo substituents), aryl or heteroaryl (whichlatter two groups are optionally substituted by one or more substituentsselected from halo, C₁₋₃ alkyl and —O—C₁₋₃ alkyl);R¹¹ and R¹² independently represent hydrogen or C₁₋₆ alkyl;

-   B¹ and B² independently represent halo (e.g. chloro or fluoro), —CN,    C₁₋₆ alkyl (optionally substituted by one or more halo (e.g. fluoro)    atoms), —OH or —O—C₁₋₆ alkyl (optionally substituted by one or more    halo (e.g. fluoro) atoms),    or a pharmaceutically acceptable salt thereof

The above-mentioned compounds of formula I (which are useful asmedicaments) may be referred to herein as “compounds of the invention”.

The compounds of the invention that may be mentioned include those ashereinbefore defined but:

-   -   (a) with the proviso that the compound is not:

or

-   -   (b) wherein Y represents:

-   -   -   (ii) —CF₃; or        -   (iii) C₃₋₆ cycloalkyl (e.g. cyclopropyl).

Pharmaceutically-acceptable salts include acid addition salts and baseaddition salts. Such salts may be formed by conventional means, forexample by reaction of a free acid or a free base form of a compound offormula I with one or more equivalents of an appropriate acid or base,optionally in a solvent, or in a medium in which the salt is insoluble,followed by removal of said solvent, or said medium, using standardtechniques (e.g. in vacuo, by freeze-drying or by filtration). Salts mayalso be prepared by exchanging a counter-ion of a compound of theinvention in the form of a salt with another counter-ion, for exampleusing a suitable ion exchange resin.

For the purposes of this invention solvates, prodrugs, N-oxides andstereoisomers of compounds of the invention are also included within thescope of the invention.

The term “prodrug” of a relevant compound of the invention includes anycompound that, following oral or parenteral administration, ismetabolised in vivo to form that compound in anexperimentally-detectable amount, and within a predetermined time (e.g.within a dosing interval of between 6 and 24 hours (i.e. once to fourtimes daily)).

For the avoidance of doubt, the term “parenteral” administrationincludes all forms of administration other than oral administration.

Prodrugs of compounds of the invention may be prepared by modifyingfunctional groups present on the compound in such a way that themodifications are cleaved, in vivo when such prodrug is administered toa mammalian subject. The modifications typically are achieved bysynthesising the parent compound with a prodrug substituent. Prodrugsinclude compounds of the invention wherein a hydroxyl, amino,sulfhydryl, carboxy or carbonyl group in a compound of the invention isbonded to any group that may be cleaved in vivo to regenerate the freehydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters andcarbamates of hydroxy functional groups, esters groups of carboxylfunctional groups, N-acyl derivatives and N-Mannich bases. Generalinformation on prodrugs may be found e.g. in Bundegaard, H. “Design ofProdrugs” p. 1-92, Elesevier, New York-Oxford (1985).

Compounds of the invention may contain double bonds and may thus existas E (entgegen) and Z (zusammen) geometric isomers about each individualdouble bond. Positional isomers may also be embraced by the compounds ofthe invention. All such isomers (e.g. if a compound of the inventionincorporates a double bond or a fused ring, the cis- and trans-forms,are embraced) and mixtures thereof are included within the scope of theinvention (e.g. single positional isomers and mixtures of positionalisomers may be included within the scope of the invention).

Compounds of the invention may also exhibit tautomerism. All tautomericforms (or tautomers) and mixtures thereof are included within the scopeof the invention. The term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerisations. Valencetautomers include interconversions by reorganisation of some of thebonding electrons.

Compounds of the invention may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/ordiastereoisomerism. Diastereoisomers may be separated using conventionaltechniques, e.g. chromatography or fractional crystallisation. Thevarious stereoisomers may be isolated by separation of a racemic orother mixture of the compounds using conventional, e.g. fractionalcrystallisation or HPLC, techniques. Alternatively the desired opticalisomers may be made by reaction of the appropriate optically activestarting materials under conditions which will not cause racemisation orepimerisation (i.e. a ‘chiral pool’ method), by reaction of theappropriate starting material with a ‘chiral auxiliary’ which cansubsequently be removed at a suitable stage, by derivatisation (i.e. aresolution, including a dynamic resolution), for example with ahomochiral acid followed by separation of the diastereomeric derivativesby conventional means such as chromatography, or by reaction with anappropriate chiral reagent or chiral catalyst all under conditions knownto the skilled person.

All stereoisomers (including but not limited to diastereoisomers,enantiomers and atropisomers) and mixtures thereof (e.g. racemicmixtures) are included within the scope of the invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms.

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature (or the most abundant one found in nature). Allisotopes of any particular atom or element as specified herein arecontemplated within the scope of the compounds of the invention.Exemplary isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, fluorine, chlorine and iodine, such as ²H, ³H, ¹¹C,¹³C, ¹⁴C, ¹³N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I.Certain isotopically-labeled compounds of the present invention (e.g.,those labeled with ³H and ¹⁴C) are useful in compound and for substratetissue distribution assays. Tritiated (³H) and carbon-14 (¹⁴C) isotopesare useful for their ease of preparation and detectability. Further,substitution with heavier isotopes such as deuterium (i.e., ²H mayafford certain therapeutic advantages resulting from greater metabolicstability (e.g., increased in vivo half-life or reduced dosagerequirements) and hence may be preferred in some circumstances. Positronemitting isotopes such as ¹⁵O, ¹³N, ¹¹C and ¹⁸F are useful for positronemission tomography (PET) studies to examine substrate receptoroccupancy. Isotopically labeled compounds of the present invention cangenerally be prepared by following procedures analogous to thosedisclosed in the Scheme 1 and/or in the Examples herein below, bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent.

Unless otherwise specified, C_(1-q) alkyl groups (where q is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of two or three, as appropriate)of carbon atoms, be branched-chain, and/or cyclic (so forming aC_(3-q)-cycloalkyl group). Such cycloalkyl groups may be monocyclic orbicyclic and may further be bridged. Further, when there is a sufficientnumber (i.e. a minimum of four) of carbon atoms, such groups may also bepart cyclic. Such alkyl groups may also be saturated or, when there is asufficient number (i.e. a minimum of two) of carbon atoms, beunsaturated (forming, for example, a C_(2-q) alkenyl or a C_(2-q)alkynyl group).

C_(3-q) cycloalkyl groups (where q is the upper limit of the range) thatmay be specifically mentioned may be monocyclic or bicyclic alkylgroups, which cycloalkyl groups may further be bridged (so forming, forexample, fused ring systems such as three fused cycloalkyl groups). Suchcycloalkyl groups may be saturated or unsaturated containing one or moredouble bonds (forming for example a cycloalkenyl group). Substituentsmay be attached at any point on the cycloalkyl group. Further, wherethere is a sufficient number (i e a minimum of four) such cycloalkylgroups may also be part cyclic.

The term “halo”, when used herein, preferably includes fluoro, chloro,bromo and iodo.

Heterocycloalkyl groups that may be mentioned include non-aromaticmonocyclic and bicyclic heterocycloalkyl groups in which at least one(e.g. one to four) of the atoms in the ring system is other than carbon(i.e. a heteroatom), and in which the total number of atoms in the ringsystem is between 3 and 20 (e.g. between three and ten, e.g between 3and 8, such as 5- to 8-). Such heterocycloalkyl groups may also bebridged. Further, such heterocycloalkyl groups may be saturated orunsaturated containing one or more double and/or triple bonds, formingfor example a C_(2-q) heterocycloalkenyl (where q is the upper limit ofthe range) group. C_(2-q) heterocycloalkyl groups that may be mentionedinclude 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo-[3.2.1]octanyl, aziridinyl,azetidinyl, dihydro-pyranyl, dihydropyridyl, dihydropyrrolyl (including2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl(including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl,imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl,6-oxabicyclo-[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl,piperidinyl, non-aromatic pyranyl, pyrazolidinyl, pyrrolidinonyl,pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl,tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl,thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including1,3,5-trithianyl), tropanyl and the like. Substituents onheterocycloalkyl groups may, where appropriate, be located on any atomin the ring system including a heteroatom. The point of attachment ofheterocycloalkyl groups may be via any atom in the ring system including(where appropriate) a heteroatom (such as a nitrogen atom), or an atomon any fused carbocyclic ring that may be present as part of the ringsystem. Heterocycloalkyl groups may also be in the N- or S-oxidisedform. Heterocycloalkyl mentioned herein may be stated to be specificallymonocyclic or bicyclic.

Aryl groups that may be mentioned include C₆₋₂₀, such as C₆₋₁₂ (e.g.C₆₋₁₀) aryl groups. Such groups may be monocyclic, bicyclic or tricyclicand have between 6 and 12 (e.g. 6 and 10) ring carbon atoms, in which atleast one ring is aromatic. C₆₋₁₀ aryl groups include phenyl, naphthyland the like, such as 1,2,3,4-tetrahydronaphthyl. The point ofattachment of aryl groups may be via any atom of the ring system. Forexample, when the aryl group is polycyclic the point of attachment maybe via atom including an atom of a non-aromatic ring. However, when arylgroups are polycyclic (e.g. bicyclic or tricyclic), they are preferablylinked to the rest of the molecule via an aromatic ring.

Unless otherwise specified, the term “heteroaryl” when used hereinrefers to an aromatic group containing one or more heteroatom(s) (e.g.one to four heteroatoms) preferably selected from N, O and S. Heteroarylgroups include those which have between 5 and 20 members (e.g. between 5and 10) and may be monocyclic, bicyclic or tricyclic, provided that atleast one of the rings is aromatic (so forming, for example, a mono-,bi-, or tricyclic heteroaromatic group). When the heteroaryl group ispolycyclic the point of attachment may be via any atom including an atomof a non-aromatic ring. However, when heteroaryl groups are polycyclic(e.g. bicyclic or tricyclic), they are preferably linked to the rest ofthe molecule via an aromatic ring. Heteroaryl groups that may bementioned include 3,4-dihydro-1H-isoquinolinyl, 1,3-dihydroisoindolyl,1,3-dihydroisoindolyl (e.g. 3,4-dihydro-1H-isoquinolin-2-yl,1,3-dihydroisoindol-2-yl, 1,3-dihydroisoindol-2-yl; i.e. heteroarylgroups that are linked via a non-aromatic ring), or, preferably,acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl(including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl,benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), benzothiazolyl,benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl(including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolyl,benzomorpholinyl, benzoselenadiazolyl (including2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl,cinnolinyl, furanyl, imidazolyl, imidazo[1,2-a]pyridyl, indazolyl,indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl,isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl,naphthyridinyl (including 1,6-naphthyridinyl or, preferably,1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl,phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl,tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl),tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl,thiophenetyl, thienyl, triazolyl (including 1,2,3-triazolyl,1,2,4-triazolyl and 1,3,4-triazolyl) and the like. Substituents onheteroaryl groups may, where appropriate, be located on any atom in thering system including a heteroatom. The point of attachment ofheteroaryl groups may be via any atom in the ring system including(where appropriate) a heteroatom (such as a nitrogen atom), or an atomon any fused carbocyclic ring that may be present as part of the ringsystem. Heteroaryl groups may also be in the N- or S-oxidised form.Heteroaryl groups mentioned herein may be stated to be specificallymonocyclic or bicyclic. When heteroaryl groups are polycyclic in whichthere is a non-aromatic ring present, then that non-aromatic ring may besubstituted by one or more ═O group.

It may be specifically stated that the heteroaryl group is monocyclic orbicyclic. In the case where it is specified that the heteroaryl isbicyclic, then it may consist of a five-, six- or seven-memberedmonocyclic ring (e.g. a monocyclic heteroaryl ring) fused with anotherfive-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroarylring).

Heteroatoms that may be mentioned include phosphorus, silicon, boronand, preferably, oxygen, nitrogen and sulfur.

For the avoidance of doubt, where it is stated herein that a group (e.g.a C₁₋₆ alkyl group) may be substituted by one or more substituents (e.g.selected from A¹), then those substituents (e.g. defined by A¹) areindependent of one another. That is, such groups may be substituted withthe same substituent (e.g. defined by A¹) or different substituents(defined by A¹).

All individual features (e.g. preferred features) mentioned herein maybe taken in isolation or in combination with any other feature(including preferred feature) mentioned herein (hence, preferredfeatures may be taken in conjunction with other preferred features, orindependently of them).

The skilled person will appreciate that compounds of the invention thatare the subject of this invention include those that are stable. Thatis, compounds of the invention include those that are sufficientlyrobust to survive isolation from e.g. a reaction mixture to a usefuldegree of purity.

Compounds of the invention that may be mentioned include those in whichthere is provided a compound of formula I as defined herein but:

-   provided that when Y represents 2-chloro-phenyl, R^(y1) represents    —OCH₂CH₃, R^(y) and R^(y2) both represent hydrogen, X¹ and X² both    represent N, Q¹ represents a direct bond, then R^(x) does not    represent —C(O)O-tert-butyl.

Preferred compounds of the invention will now be described.

Preferred compounds of the invention include those in which:

-Q¹-R^(x) does not represent —CH₃;

for instance, when X represents —N—, and Q¹ represents a direct bond,and R^(x) represents alkyl, then, it preferably represents C₂₋₆ (e.g.C₃₋₆) alkyl (optionally substituted by one or more substituents selectedfrom ═O and A¹);

when X represents —N— and Q¹ represents a direct bond, then R^(x)preferably represents C₂₋₆ (e.g. C₃₋₆) alkyl (optionally substituted byone or more substituents selected from ═O and A¹), aryl or heteroaryl(which latter two groups are optionally substituted by one or moresubstituents selected from A² and A³, respectively);when R^(x) represents alkyl, then it preferably represents C₂₋₆ (e.g.C₃₋₆) alkyl (optionally substituted by one or more substituents selectedfrom ═O and A¹).

Preferred compounds of the invention include those in which:

the following substructure of formula I:

is one in which, preferably:none, one or two of N^(v), N^(w), N^(x), N^(y) and N^(z) (preferablyone, N^(x) or N^(y)) represents —N═ and the others represent —C(H)═ or,e.g. in the case when the above ring represents phenyl, one of N^(v),N^(w), N^(x), N^(y) and N^(z) represents —C(A⁴)=;when two of N^(v), N^(w), N^(x), N^(y) and N^(z) represent —N═, then itis preferably N^(w) and N^(y) (so forming a 5-pyrimidinyl group);n represents 0, 1 or 2 (but preferably represents 0);A⁴ (which may be present on any of the carbon atoms of the aromaticring, including when N^(x)/N^(y)/N^(z) represents —C(H)═) representshalo (e.g. fluoro or bromo), —CN, —OC₁₋₃ alkyl (e.g. —OCH₃),—S(O)₂C₁₋₃alkyl, or C₁₋₃ alkyl (optionally containing an unsaturation,so forming e.g. —C≡C), although A⁴ is preferably not present; morepreferably, the above sub-structure represents pyrimidinyl or pyridyl(preferably, pyridyl), optionally substituted by one or moresubstituents selected from A⁴; most preferably, the above sub-structurerepresents pyridyl (preferably unsubstituted pyridyl, e.g. 2-pyridyl or,preferably, 3-pyridyl or 4-pyridyl) or substituted phenyl.

In one embodiment of the invention:

Y represents the N^(v) to N^(z)-ring as defined herein (this is the mostpreferred).

In another embodiment of the invention:

Y represents —N(C₁₋₆ alkyl)₂ (e.g. —N(CH₃)₂).

In another embodiment of the invention:

Y represents C₃₋₆ cycloalkyl (e.g. cyclopropyl).

In another embodiment of the invention:

Y represents —CF₃.

More preferred compounds of the invention include those in which:

when X¹ represents —N—, Q¹ represents a direct bond;

X² represents —C(H)— and X¹ represents —N— (so forming a 4-piperidinylgroup);

X² represents —N— and X¹ represents —C(H)— (so forming a 1-piperidinylgroup);

X¹ and X² represent —N—, so forming a piperazinyl group.

Further preferred compounds of the invention include those in which:

A¹ represents heterocycloalkyl (e.g. oxetanyl) or, more preferably, A¹represents halo (e.g. fluoro), —CN, C₁₋₆ alkyl (e.g. C₃₋₆ cycloalkyl),aryl (optionally substituted by one or more (e.g. one) substituent(s)selected from B¹), heteroaryl (optionally substituted by one or more(e.g. one) substituent(s) selected from B²) or —OR¹;when A¹ represents aryl, then it is preferably phenyl optionallysubstituted by one or more (e.g. one or two) substituent(s) selectedfrom B¹;when A¹ represents aryl substituted by one or more (e.g. one) B¹substituent(s), then there is at least one substituent located at themeta-position of the phenyl group (and in total, there is preferably oneor two B¹ substituents);when A¹ represents optionally substituted heteroaryl, it is preferably a5- or 6-membered heteroaryl group preferably containing one, two orthree (e.g. one) heteroatom(s) preferably selected from nitrogen, sulfurand oxygen (e.g. sulfur and/or oxygen), so forming e.g. a thienyl (e.g.2-thienyl or 3-thienyl) or a furanyl (e.g. 2-furanyl) group;when A¹ represents optionally substituted heteroaryl, then it isoptionally substituted by one or two (e.g. one) substituent(s) selectedfrom B²;when A¹ represents C₃₋₆ cycloalkyl, then it is preferably cyclohexyl;B¹ represents halo (e.g. fluoro or chloro), —CN, —OH or C₁₋₃ alkyl(methyl; optionally substituted by one or more halo, e.g. fluoro, atoms,so forming e.g. a —CF₃ group);B² preferably represents C₁₋₄ alkyl (e.g. C₁₋₂ alkyl such as methyl);A¹ represents halo (e.g. fluoro), —CN, thienyl (e.g. 2- or 3-thienyl,such as 3-methyl, 2-thienyl or unsubstituted 3-thienyl), furanyl (e.g.2-furanyl), C₃₋₆ cycloalkyl (e.g. cyclohexyl) or —O-phenyl;R¹ represents aryl (e.g. unsubstituted phenyl);when Q¹ represents —N(R^(z))—, then R^(x) represents C₁₋₆ alkyl(optionally substituted by one or more substituents selected from ═O andA¹), so forming e.g. —C(O)—C(H)(CH₃)—O-phenyl;R^(z) represents hydrogen;when Q¹ represents a direct bond or —C(O)—, then R^(x) preferablyrepresents:C₁₋₆ alkyl (e.g. acyclic C₁₋₆ alkyl or C₃₋₆ cycloalkyl) optionallysubstituted by one or more substituents selected from ═O and/or A¹, andoptionally containing one or more (e.g. one) double bond (so forming aC₂₋₆ alkenyl group) or triple bond (so forming a C₂₋₆ alkynyl group), soforming e.g. —CH₂—C(CH₃)₃, —CH₂CH(CH₃)₂, cyclopropyl, —CH₂—CF₃,—CH₂—C(H)F₂, —CH₂C(CH₃)₂—CN, —C(O)—C(CH₃)₃, —CH₂—CF₂CH₃, —CH₂-[3-methyl,2-thienyl], —CH₂—C(CH₃)═CHCH₃, —CH₂-[3-fluorophenyl], —CH₂-[3-thienyl],—CH₂-[3-chloro-6-OH-phenyl], —CH₂-[3-hydroxyphenyl],—CH₂-[2-hydroxyphenyl], —CH₂-[2-hydroxy-4-chloro-phenyl],—CH₂-[2-hydroxy-5-chlorophenyl], —CH₂-phenyl, —CH₂-cyclohexyl,—CH₂-[2-thienyl], —CH₂[2-furanyl], —C(O)—C(H)(CH₃)—O-phenyl,—CH₂—C(H)(CH₃)₂, -cyclopropyl, —CH₂-[4-fluorophenyl], —C(O)—C(CH₃)₃,—CH₂-(3-trifluoromethyl-phenyl), —CH₂-(3-cyanophenyl),—CH₂-(4-cyanophenyl), —CH₂-(2,4-difluorophenyl), —CH₂-(3-methylphenyl),—CH₂-(4-methylphenyl), —CH₂-(2-fluorophenyl), —CH₂-(2-cyanophenyl),—CH₂-(3,4-difluorophenyl), —CH₂-(4-chlorophenyl), —CH₂-(3-chlorophenyl),—CH₂-(2-trifluoromethyl-phenyl), —CH₂-(2,6-difluorophenyl),—CH₂-(3,5-difluorophenyl), —CH₂—C≡CH or —CH₂—C(CH₂)(3-oxetanyl) (mostpreferably, R^(x) represents —CH₂—C(CH₃)₃, —CH₂—CF₃, —CH₂—C(H)F₂,—CH₂C(CH₃)₂—CN, —C(O)—C(CH₃)₃ or —CH₂—CF₂CH₃); orR^(x) represents aryl (e.g. phenyl) optionally substituted by one ormore (e.g. one or two) substituents selected from A², so forming fore.g. unsubstituted phenyl;R¹⁰ represents C₁₋₄ alkyl (e.g. C₁₋₂ alkyl, such as methyl);R¹¹ and R¹² independently represent hydrogen or, preferably, C₁₋₃ alkyl(e.g. methyl); either all of R^(y), R^(y1) and R^(y2) represent hydrogenor, more preferably, at least one of R^(y), R^(y1) and R^(y2)(preferably R^(y)) represents a substituent other than hydrogen and theothers (preferably R^(y1) and R^(y2)) represents hydrogen (i.e. there ispreferably one substituent present on the phenyl ring, preferably in themeta-position); when one of R^(y), R^(y1) and R^(y2) (e.g. R^(y))represents a substituent, then it is preferably selected from halo,—OCH₃, —N(CH₃)₂, —CN or C₁₋₃ alkyl optionally substituted by one or morefluoro atoms;R^(y) represents hydrogen or, preferably, halo (e.g. fluoro or,preferably, chloro), —OCH₃, —N(CH₃)₂, —CN or C₁₋₃ alkyl (e.g. —CH₃)optionally substituted by one or more fluoro atoms (e.g. —CF₃), and mostpreferably, R^(y) represents —OCH₃ or —CN;R^(y1) represents hydrogen, or, when R^(y) represents hydrogen, mayrepresent a substituent selected from —OCH₃ and C₁₋₃ alkyl (e.g.methyl);R^(y2) represents hydrogen, or, when R^(y) and R^(y1) representhydrogen, may represent a substituent selected from halo (e.g. fluoro)and C₁₋₃ alkyl (e.g. methyl);R¹ represents hydrogen;A² and A³ independently represent halo (e.g. chloro) or —OR¹ (e.g. —OH).

Certain compounds of the invention disclosed herein may be novel per se.And hence in a further embodiment of the invention, there is provided acompound of formula I:

but wherein:Y represents:

none or one of N^(v), N^(w), N^(x), N^(y) and N^(z) (preferably one,e.g. N^(x) or N^(y)) represent(s) —N═ and the others represent —C(H)═;n represents 0 or 1;X¹ and X² independently represent —N— or —C(H)—;when X¹ represents —N—, Q¹ represents a direct bond;when X¹ represents —C(H)—, Q¹ represents a direct bond or —N(R^(z))—;R^(z) represents hydrogen or C₁₋₆ alkyl;R^(x) represents C₁₋₆ alkyl (optionally substituted by one or moresubstituents selected from ═O and A¹), aryl or heteroaryl (which lattertwo groups are each optionally substituted by one or more substituentsselected from A² and A³, respectively);R^(y), R^(y1) and R^(y2) independently represent hydrogen, halo, —CN,—OR¹⁰, —N(R¹¹)(R¹²) or C₁₋₆ alkyl (optionally substituted by one or morehalo (e.g. fluoro) atoms);A¹, A², A³ and A⁴ independently represent halo, —CN, —OR¹,—S(O)₀₋₂C₁₋₃alkyl, C₁₋₆ alkyl (optionally substituted by one or morehalo substituents), heterocycloalkyl (optionally substituted by one ormore substituents selected from C₁₋₃ alkyl and halo), aryl or heteroaryl(which latter two groups are optionally substituted by one or moresubstituents selected from B¹ and B², respectively);each R¹ and R¹⁰ independently represent hydrogen, C₁₋₆ alkyl (optionallysubstituted by one or more halo substituents), aryl or heteroaryl (whichlatter two groups are optionally substituted by one or more substituentsselected from halo, C₁₋₃ alkyl and —O—C₁₋₃ alkyl);R¹¹ and R¹² independently represent hydrogen or C₁₋₆ alkyl;B¹ and B² independently represent halo (e.g. chloro or fluoro), —CN,C₁₋₆ alkyl (optionally substituted by one or more halo (e.g. fluoro)atoms), —OH or —O—C₁₋₆ alkyl (optionally substituted by one or more halo(e.g. fluoro) atoms),or a pharmaceutically acceptable salt thereof, with the proviso that thecompound is not:

Preferred novel compounds of the invention in accordance with thisfurther aspect of the invention may be those mentioned hereinbefore butin which:

X¹ represents —N—;

X² represent —C(H)—;

R^(x) represents C₁₋₆ alkyl (optionally substituted by one or moresubstituents selected from ═O and A¹);

A⁴ (which is preferably present on a carbon atom of the phenyl ring, andis preferably in the para-position) represents halo (e.g. fluoro), —CNor —OC₁₋₃ alkyl (e.g. —OCH₃); A¹ represents halo (e.g. fluoro), —CN,C₁₋₆ alkyl or —OR¹;

either all of R^(y), R^(y1) and R^(y2) represent hydrogen or, morepreferably, at least one of R^(y),

R^(y1) and R^(y2) (preferably R^(y)) represents a substituent other thanhydrogen and the others (preferably R^(y1) and R^(y2)) representshydrogen (i.e. there is preferably one substituent present on the phenylring, preferably in the meta-position);

when R^(y) is other than hydrogen, it preferably represents halo (e.g.chloro), —OCH₃ or —CN; and/or

R¹ represents hydrogen.

In particular, preferred novel compounds of the invention may be thefollowing:

or a pharmaceutically acceptable salt thereofPharmacology

The compounds according to the invention have surprisingly been shown tobe suitable for the treatment of a certain non-mycobacterial infection,specifically Staphylococcus aureus. They are therefore useful asmedicaments/pharmaceuticals.

Further, the present invention also relates to the use of the compoundsof the invention, the pharmaceutically acceptable salts thereof or theN-oxide forms thereof, as well as any of the pharmaceutical compositionsthereof as described hereinafter, for the manufacture of a medicamentfor the treatment of a certain non-mycobacterial infection, specificallyStaphylococcus aureus.

Accordingly, in another aspect, the invention provides a method oftreating a patient suffering from, or at risk of, a certainnon-mycobacterial infection, specifically Staphylococcus aureus, whichcomprises administering to the patient a therapeutically effectiveamount of a compound or pharmaceutical composition according to theinvention.

Compounds of the invention have not only been shown to be suitable forthe treatment of a certain non-mycobaterium, Staphylococcus aureus, buthave been shown to selective activity against it. Hence, where“treatment” of a certain non-mycobacterium is referred to herein, itpreferably means “selective treatment”, for instance it has activityagainst that bacterium (Staphylococcus aureus) but may have no orminimal (or less) activity against other bacteria. This may beadvantageous as, if the compound/drug is only selective againstStaphylococcus aureus, then resistance to other strains cannot be builtup and the need for unnecessary antibacterial action is prevented.

Bacterial infections which may be treated by the present compoundsinclude, for example, central nervous system infections, external earinfections, infections of the middle ear, such as acute otitis media,infections of the cranial sinuses, eye infections, infections of theoral cavity, such as infections of the teeth, gums and mucosa, upperrespiratory tract infections, lower respiratory tract infections,genitourinary infections, gastrointestinal infections, gynaecologicalinfections, septicemia, bone and joint infections, skin and skinstructure infections, bacterial endocarditis, burns, antibacterialprophylaxis of surgery, and antibacterial prophylaxis inimmunosuppressed patients, such as patients receiving cancerchemotherapy, or organ transplant patients.

Whenever used hereinbefore or hereinafter, that the compounds can treata bacterial infection it is meant that the compounds can treat aninfection with a certain non-mycobacterial infection, specificallyStaphylococcus aureus.

The invention also relates to a composition comprising apharmaceutically acceptable carrier and, as active ingredient, atherapeutically effective amount of a compound according to theinvention. The compounds according to the invention may be formulatedinto various pharmaceutical forms for administration purposes. Asappropriate compositions there may be cited all compositions usuallyemployed for systemically administering drugs. To prepare thepharmaceutical compositions of this invention, an effective amount ofthe particular compound, optionally in addition salt form, as the activeingredient is combined in intimate admixture with a pharmaceuticallyacceptable carrier, which carrier may take a wide variety of formsdepending on the form of preparation desired for administration. Thesepharmaceutical compositions are desirable in unitary dosage formsuitable, in particular, for administration orally or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed such as, forexample, water, glycols, oils, alcohols and the like in the case of oralliquid preparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% by weight, more preferablyfrom 0.1 to 70% by weight, even more preferably from 0.1 to 50% byweight of the active ingredient(s), and, from 1 to 99.95% by weight,more preferably from 30 to 99.9 by weight %, even more preferably from50 to 99.9 by weight % of a pharmaceutically acceptable carrier, allpercentages being based on the total composition.

The pharmaceutical composition may additionally contain various otheringredients known in the art, for example, a lubricant, stabilisingagent, buffering agent, emulsifying agent, viscosity-regulating agent,surfactant, preservative, flavouring or colorant.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage.

Unit dosage form as used herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such unit dosage forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,suppositories, injectable solutions or suspensions and the like, andsegregated multiples thereof. The daily dosage of the compound accordingto the invention will, of course, vary with the compound employed, themode of administration, the treatment desired and the mycobacterialdisease indicated. However, in general, satisfactory results will beobtained when the compound according to the invention is administered ata daily dosage not exceeding 1 gram, e.g. in the range from 10 to 50mg/kg body weight.

Given the fact that the compounds of the invention are active againstbacterial infections (e.g. a certain type as defined herein), thepresent compounds may be combined with other antibacterial agents inorder to effectively combat bacterial infections.

Therefore, the present invention also relates to a combination of (a) acompound according to the invention, and (b) one or more otherantibacterial agents.

The present invention also relates to a combination of (a) a compoundaccording to the invention, and (b) one or more other antibacterialagents, for use as a medicine.

The present invention also relates to the use of a combination orpharmaceutical composition as defined directly above for the treatment(e.g. selective treatment) of a bacterial infection (e.g. a certain typeas defined herein, Staphylococcus aureus).

A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and, as active ingredient, a therapeutically effective amount of(a) a compound according to the invention, and (b) one or more otherantibacterial agents, is also comprised by the present invention,particularly for use in the treatment of a certain bacterial infectionas defined herein.

The weight ratio of (a) the compound according to the invention and (b)the other antibacterial agent(s) when given as a combination may bedetermined by the person skilled in the art. Said ratio and the exactdosage and frequency of administration depends on the particularcompound according to the invention and the other antibacterial agent(s)used, the particular condition being treated, the severity of thecondition being treated, the age, weight, gender, diet, time ofadministration and general physical condition of the particular patient,the mode of administration as well as other medication the individualmay be taking, as is well known to those skilled in the art.Furthermore, it is evident that the effective daily amount may belowered or increased depending on the response of the treated subjectand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention. A particular weight ratio for thepresent compound of formula (Ia) or (Ib) and another antibacterial agentmay range from 1/10 to 10/1, more in particular from 1/5 to 5/1, evenmore in particular from 1/3 to 3/1.

The compounds according to the invention and the one or more otherantibacterial agents may be combined in a single preparation or they maybe formulated in separate preparations so that they can be administeredsimultaneously, separately or sequentially. Thus, the present inventionalso relates to a product containing (a) a compound according to theinvention, and (b) one or more other antibacterial agents, as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of a bacterial infection.

General Preparation

The compounds according to the invention can generally be prepared by asuccession of steps, each of which is known to the skilled person and/ordescribed below in the following General Schemes:

It is considered within the knowledge of the skilled man to explore theappropriate temperatures, dilutions, and reaction times in order tooptimize the above reactions in order to obtain a desired compound.

The compounds of formula I may be converted to the corresponding N-oxideforms following art-known procedures for converting a trivalent nitrogeninto its N-oxide form. Said N-oxidation reaction may generally becarried out by reacting the starting material of formula I with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarbo-peroxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert.butyl hydro-peroxide. Suitable solvents are, for example, water,lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

For instance, compounds of formula I in which Y represents the N^(v) toN^(z)-containing ring may be prepared by the following methods:

-   (i) For compounds of formula I in which X¹ represents —N—, reaction    of a compound of formula II,

-   -   wherein N^(v), N^(w), N^(x), N^(y), N^(z), X², R^(y), R^(y1),        R^(y2), A⁴ and n are as hereinbefore defined, with:

-   (a) a compound of formula III,    L¹-Q¹-R^(x)  III    -   wherein L¹ represents a suitable leaving group, such as chloro,        bromo, iodo or a sulfonate group;

-   (b) for compounds of formula I in which Q¹ represents a direct bond    and R^(x) represents a group attached to Q¹ with a —CH₂—R^(xx)    moiety (in which, collectively, this group represents the R^(x)    moiety),    O═C(H)(R^(xx))  IV    -   wherein R^(xx) represents a part of the R^(x) moiety (R^(x)        being hereinbefore defined), and which reaction is performed        under reductive amination reaction conditions, for instance        conditions known to those skilled in the art, e.g. as a reaction        in “one pot”, for instance in the presence of a selective        reducing agent (which reduces the imine intermediate, but not        the aldehyde starting material) such as sodium cyanoborohydride        or, preferably, sodium triacetoxyborohydride, for instance in        the presence of a mild acid (e.g. acetic acid), in a suitable        solvent (e.g. dichloromethane). Alternative conditions may also        be employed, for instance, first a condensation reaction,        followed by reaction in the presence of a reducing agent (which        need not be “imine” selective, e.g. sodium borohydride may be        employed when the reaction is performed in two steps);

-   (ii) for compounds of formula I in which the requisite pyrimidine is    attached to X² in which X² represents —N—, reaction of a compound of    formula V,

-   -   wherein L² represents a suitable leaving group, such as halo        (e.g. chloro), with a compound of formula VI

-   -   wherein X¹, Q¹ and R^(x) are as hereinbefore defined, under        aromatic nucleophilic substitution reaction conditions, for        instance such as those known in the art, e.g. in the presence of        a base (such as an organic base, e.g. a dialkylamine base, for        instance N,N-diispropylethylamine);

-   (iii) for compounds in which there is a —CH₂— moiety present,    reduction of a corresponding compound in which there is a —C(O)—    moiety present, in the presence of a suitable reducing agent, e.g.    LiAlH₄;

-   (iv) reaction with a compound of formula VII,

-   -   wherein L³ represents a suitable leaving group (preferably an        amino moiety, such as —N(CH₃)₂), and the integers (e.g. R^(y),        R^(y1), R^(y2), Q¹, R^(x), X¹ and X²)) are as hereinbefore        defined, with a compound of formula VIII,

-   -   or a derivative thereof (e.g. a salt, such as a HCl salt), in        which the integers (e.g. N^(v), N^(w), N^(x), N^(y), N^(z), A⁴        and n are as hereinbefore defined), under reaction conditions        that promotes the cyclisation (e.g. in the presence of a base,        such as an inorganic base e.g. tBuOK, and a suitable solvent        such as an alcoholic solvent, e.g. ethanol, which reaction may        be performed at elevated temperature);

-   (v) for compounds containing a —C(F)₂— moiety, reaction of a    corresponding compound containing a —C(O)-moiety, by reaction with    an appropriate “fluoride” reagent (e.g. diethyl amino sulfur    trifluoride; e.g. in the presence of a suitable solvent such as    dichloromethane).

Compounds of formula II may be prepared by reaction of a compound offormula IX,

or a derivative thereof (such as a protected derivative, e.g. protectedon the —N(H)-moiety with e.g. a Boc group) wherein the integers (e.g.L³, R^(y), R^(y1), R^(y2), Q¹, R^(x) and X²) are as hereinbefore definedwith a compound of formula VIII as hereinbefore defined.

Compounds of formula V may be prepared in accordance with the proceduresdescribed herein.

Compounds of VII and IX may be prepared by reaction of a correspondingcompound of formula X,

wherein X^(1a) represents —X¹-Q¹-R^(x) (in the case of preparation ofcompounds of formula VII) or —N(H)— (in the case of preparation ofcompounds of formula IX, or a protected moiety thereof, e.g. —N(Boc)-)and the other integers (e.g. X², R^(y), R^(y1) and R^(y2)) are ashereinbefore defined, with a compound of formula XI,O═C(H)-L³  XIin which L³ is as hereinbefore defined (and in particular, represents anamino group, such as —N(CH₃)₂ so forming e.g. DMF), for instancereaction of DMF-DMA in the presence of a suitable solvent (e.g. anaromatic solvent, such as toluene) at reflux.

Compounds of formula X may be prepared in accordance with the proceduresdescribed herein.

It is evident that in the foregoing and in the following reactions, thereaction products may be isolated from the reaction medium and, ifnecessary, further purified according to methodologies generally knownin the art, such as extraction, crystallization and chromatography. Itis further evident that reaction products that exist in more than oneenantiomeric form, may be isolated from their mixture by knowntechniques, in particular preparative chromatography, such aspreparative HPLC, chiral chromatography. Individual diastereoisomers orindividual enantiomers can also be obtained by Supercritical FluidChromatography (SCF).

The starting materials and the intermediates are compounds that areeither commercially available or may be prepared according toconventional reaction procedures generally known in the art.

The following examples illustrate the present invention without beinglimited thereto.

Experimental Part

1. Synthesis of Intermediate B-1:

To a solution of A-1 (100 g, 0.64 mol) and Et₃N (64.37 g, 0.64 mol) inTHF (1000 mL) was added Boc₂O (138.82 g, 0.64 mol) at 0° C., the mixturewas stirred at room temperature for 16 hrs. Then the reaction mixturewas poured into H₂O (1000 mL) and extracted with EtOAc (500 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated in vacuum to give intermediate B-1 (138.10 g, yield: 84%).

2. Synthesis of Intermediate C-1:

To a solution of B-1 (138 g, 0.54 mol) in 1 L of THF and 1 L of H₂O wasadded LiOH.H₂O (67.51 g, 1.61 mol) at 0° C. After the addition, themixture was stirred at 25° C. for 15 hrs. The organic solvent wasremoved under reduced pressure. The mixture was extracted with EtOAc(500 mL×3), and the aqueous layer was separated and treated with 0.5 Maq. HCl to adjust to pH=3 and extracted with CH₂Cl₂ (1 L×3). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated to give intermediate C-1 (80 g, 65%) as a white solid.

3. Synthesis of Intermediate D-1:

To a stirred solution of C-1 (80 g, 0.35 mol) in 1 L of anhydrous CH₂Cl₂was added CDI (62.24 g, 0.38 mol) under N₂ at 0° C. After the addition,the mixture was stirred at 25° C. for 1 hour, gas formation wasobserved. Et₃N (42.37 g, 42 mol) was added, the mixture was stirred at25° C. for 30 min, then O,N-dimethylhydroxylamine hydrochloride (42.54g, 0.44 mol) was added. After the addition, the mixture was stirred at25° C. for 15 hrs. The mixture was washed with water, aq. NaHCO₃ and aq.citric acid monohydrate. The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated to get intermediate D-1 (80 g, 95%) asa white solid.

4. Synthesis of Intermediate F-1:

To a stirred solution of D-1 (20 g, 73.44 mmol) in 500 mL of anhydrousTHF was added E-1 (350 mL, 88 mmol) under N₂ at 0° C. After theaddition, the mixture was stirred at 0° C. for 2 hours and 15° C. for 6hours. Then the mixture was filtered. The solid was dissolved in NH₄Cl(100 mL) and extracted with EtOAc (200 mL×2). The combined organiclayers were washed with brine (200 mL×2), dried over MgSO₄, filtered andconcentrated to obtain 16.2 g of intermediate F-1 as white solid.

5. Synthesis of Intermediate G-1:

A stirred solution of F-1 (15 g, 45 mmol) and DMF-DMA (9 mL, 67.48 mol)in 300 mL of anhydrous toluene was stirred at 110° C. under N₂ for 4 h.Then the solvent was evaporated under reduced pressure to obtain 12.15 gof intermediate G-1.

6. Synthesis of Intermediate I-1:

To a stirred solution of G-1 (2.5 g, 6.4 mmol) in ethanol (24 mL) wasadded, at room temperature isonicotinimidamide hydrochloride H-1 (1.5 g,9.65 mmol) followed by potassium tert-butoxide (1.44 g, 12.9 mmol).

The reaction mixture was then heated at 80° C. for 16 hours. After 100%consumption of G-1 (monitoring by LCMS), the reaction mixture wasallowed to cool to room temperature and concentrated in vacuum. Theresidue was, then, diluted with dichloromethane (150 mL) and treatedwith water (150 mL). The aqueous crude mixture was extracted withdichloromethane (2×150 mL). The combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuum. The crude compoundwas then purified on silica gel using dichloromethane/ethyl acetate:50/50 to afford the desired intermediate I-1 as a light white solid(2.58 g, 90% yield).

7. Synthesis of Intermediate J-1:

To a solution of I-1 (2.8 g, 6.25 mmol) in dichloromethane (31 mL),trifluoroacetic acid (5.7 mL) was added at room temperature. Thereaction mixture was then stirred at room temperature for 3 hours. Aftercomplete consumption of I-1 (monitoring by TLC), the reaction mixturewas concentrated in vacuum to get a residue that was taken up indichloromethane (100 mL) and treated with a saturated aqueous solutionof potassium carbonate (100 mL). The aqueous crude mixture was extractedwith dichloromethane (2×100 mL). The combined organic layers were driedover sodium sulfate, filtered and concentrated in vacuum to afford thedesired intermediate J-1 as a beige solid (2 g, 92%) which was used inthe next step without any further purification.

1. Synthesis of Intermediate L-1:

To a stirred solution of D-1 (30 g, 104 mmol) in 500 mL of anhydrous THFwas added K-1 (500 mL, 125 mmol) under N₂ at 0° C. The mixture wasstirred at 15° C. for 18 h. The reaction mixture was diluted with NH₄Cl(250 mL) and EtOAc (500 mL). The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated. The residue was purified bychromatography on silica gel (Petroleum ether:Ethylacetate=20:1) toobtain 15.12 g of intermediate L-1.

2. Synthesis of Intermediate M-1:

The mixture of L-1 (14.20 g, 37.14 mmol), Zn(CN)₂ (6.54 g, 55.72 mmol)and Pd(PPh₃)₄ (2.15 g, 1.86 mmol) in DMF (140 mL) was stirred at 100° C.for 18 h. A solution of NaHCO₃ (200 mL) was added after the mixture wascooled to the room temperature. The resulting mixture was extracted withEtOAc (200 mL×2). The combined organic layers were washed with NaHCO₃(100 mL), brine (100 mL), dried over MgSO₄, filtered and concentrated.The residue was purified by chromatography on silica gel (Petroleumether:Ethylacetate=10:1) to obtain intermediate M-1 (12.04 g) as a whitesolid.

3. Synthesis of Intermediate N-1:

A stirred solution of M-1 (12.00 g, 36.54 mmol) and DMF-DMA (6.53 g,58.81 mmol) in 300 mL of anhydrous toluene was stirred at 110° C. for 4h under N₂. Then the solvent was evaporated under reduced pressure. Theresidue was purified by chromatography on silica gel (Petroleumether:Ethylacetate=1:1) to obtain intermediate N-1 (10.05 g) as a whitesolid.

4. Synthesis of Compound P-1:

To a stirred solution of N-1 (800 mg, 2.0 mmol) in acetonitrile (8 mL)at room temperature, isonicotinimidamide hydrochloride H-1 (657 mg, 4.1mmol) was added followed by DBU (0.93 mL, 6.2 mmol). The reactionmixture was then heated in a sealed tube at 110° C. for 16 hours. Aftercomplete consumption of N-1 (monitoring by LCMS), the reaction mixturewas allowed to cool to room temperature and treated with water (30 mL).The aqueous crude mixture was extracted with dichloromethane (3×30 mL).The combined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuum. The crude compound (1.3 g) was then purified onsilica gel using dichloromethane/methanol/ammonium hydroxide solution(33% in H₂O): 98/2/0.1 to afford the desired intermediate O-1 as a lightyellow solid (800 mg, 87% yield).

5. Synthesis of Intermediate P-1:

To a solution of 0-1 (800 mg, 1.8 mmol) in dichloromethane (10 mL) wasadded, at room temperature, trifluoroacetic acid (2.15 mL). The reactionmixture was then stirred at room temperature for 2 hours. After completeconsumption of 0-1 (monitoring by TLC), the reaction mixture was treatedwith a saturated aqueous solution of sodium carbonate (30 mL). Theaqueous crude mixture was extracted with dichloromethane (3×30 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuum to afford the desired intermediate P-1 as a lightyellow solid (695 mg, quantitative yield) which was used in the nextstep without any further purification.

1. Synthesis of Intermediate R-1:

A mixture of Q-1 (150 g, 1.53 mol) and pyridinium tribromide (635 g,1.99 mol) in CH₂Cl₂ (2 L) was stirred at 20° C. for 96 hours. Then thereaction mixture was washed with an aqueous solution of Na₂S₂O₃ (2×1 L)and brine (1 L), dried over MgSO₄, filtered and concentrated to giveintermediate R-1 (380 g, 96%) as yellow liquid.

2. Synthesis of Intermediate S-1:

To a mixture of R-1 (170 g, 1.08 mol), H-1 (334.00 g, 1.29 mol) andNaHCO₃ (362.45 g, 4.31 mol) in 2.5 L of anhydrous MeOH was stirred at80° C. for 12 hrs under N₂. Then the mixture was cooled and filtered,the filtrate was concentrated. The residue was purified bychromatography on silica gel (CH₂Cl₂:MeOH=10:1) to obtain intermediateS-1 (170 g) as a brown solid.

3. Synthesis of Intermediate U-1:

A stirred mixture of S-1 (150 g, 595.08 mmol) and T-1 (131.16 g, 892.62mmol) in 1500 mL of EtOH and 300 mL of H₂O was added NaHCO₃ (189.21 g,1.79 mol) and Pd(PPh₃)₂Cl₂ (15 g) under N₂. The reaction mixture wasstirred at 60° C. for 8 hrs under N₂. Then the mixture was filtered andthe solvent was evaporated under reduced pressure. The residue waswashed with EtOAc to give intermediate U-1. The crude compound was useddirectly in the next step.

4. Synthesis of Intermediate V-1:

A stirred suspension of U-1 (100 g, crude) in 1500 mL of anhydrousCH₂Cl₂ was added dropwise oxalyl dichloride (462.77 g, 3.65 mol) at 0°C. under N₂. Then DMF (53.30 g, 7.29 mol) was added and the reactionmixture was stirred at 15° C. for 4 h under N₂. Then the solvent wasevaporated under reduced pressure. The residue was dissolved in EtOAc (1L) and an aqueous of NaHCO₃ (1 L). The organic layer was washed withbrine, dried over MgSO₄ and concentrated. The residue was purified bychromatography on silica gel (CH₂Cl₂:MeOH=20:1) to obtain the crudeproduct. The crude product was washed with EtOH to give 9.4 g ofintermediate V-1 as a brown solid, and was used directly in the nextstep.

Synthesis of Final Compound 6:

To a solution of J-1 (250 mg, 0.722 mmol) in dichloroethane (10 mL),acetic acid (0.124 mL, 2.17 mmol) and 2,2-dimethylpropanal (0.157 mL,1.45 mmol) were added. The reaction mixture was then stirred at roomtemperature for 2 hours. Sodium triacetoxyborohydride (428 mg, 2 mmol)was then added and the mixture was stirred at room temperature for 3 h.In order to complete the reaction, 2,2-dimethylpropanal (0.157 mL, 1.45mmol) and acetic acid (0.124 mL, 2.17 mmol) were added and the mixturewas stirred at room temperature for 1 h before adding sodiumtriacetoxyborohydride (428 mg, 2 mmol). Reaction mixture was stirred atroom temperature for 12 hours and then diluted with dichloromethane andtreated with a saturated solution of sodium bicarbonate. The aqueouslayer was extracted with dichloromethane. The combined organic layerswere dried over sodium sulfate, filtered and concentrated in vacuum. Thecrude compound was then purified on silica gel usingdichloromethane/methanol/ammonium hydroxide solution (33% in H₂O):98/2/0.1 to afford the desired compound 6 as a white solid (156 mg, 52%yield).

Synthesis of Final Compound 9:

To a solution of J-1 (0.15 g, 0.433 mmol) and4-chloro-2-hydroxybenzaldehyde (0.068 g, 0.433 mmol) in dichloromethane(4 mL) under N₂-atmosphere was added sodium triacetoxyborohydride (0.138g, 0.649 mmol) in one portion. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was directly loaded on apreparative TLC and eluted four times with [heptane(1):EtOAc(2)]. Themain band was scratched off, and eluted from the SiO₂ with[EtOAc(9):MeOH(1)]. The elute was evaporated until dryness to yield0.139 g of compound 9 (66%).

Synthesis of Final Compound 12:

To a solution of J-1 (0.1 g, 0.289 mmol) in methanol (extra dry) (3 mL)and acetic acid (0.1 mL) under N₂-atmosphere was added(1-ethoxycyclopropoxy)trimethylsilane (0.061 mL, 0.303 mmol) in oneportion. The reaction mixture was stirred at room temperature for 0.5 h,then sodium cyanoborohydride (0.027 g, 0.433 mmol) was added and thereaction mixture was heated to reflux overnight, then allowed to cool toroom temperature and stirred 24 h. The reaction mixture was directlyloaded on a preparative TLC and eluted with [CH₂Cl₂ (95):MeOH (5)]. Themain band was scratched off, and eluted from the SiO₂ with [EtOAc(9):MeOH (1)]. The elutes were evaporated until dryness to yield 0.089 gof final compound 12 (54%).

Synthesis of Final Compound 20:

A mixture of J-1 (100 mg, 0.289 mmol), 2-phenoxypropionic acid (62.4 mg,0.375 mmol), EDCI (83 mg, 0.433 mmol), HOBT (58.5 mg, 0.433 mmol) andNEt₃ (61 μL, 0.433 mmol) in CH₂Cl₂ (5 mL) was stirred at RT overnight.Water was added and the layers were decanted. The organic layer waswashed with water, dried over MgSO₄, filtered and the solvent wasevaporated. The crude compound was purified by chromatography oversilica gel (15-40 μm, 30 g) with CH₂Cl₂/MeOH/NH₄OH 97.5/2.5/0.1. Thesolvent was evaporated to give final compound 20 (64%).

Synthesis of Final Compound 21:

Intermediate W-1 was synthesized according to the procedure describedfor intermediate V-1, using (3-methoxyphenyl)boronic acid instead ofT-1. A solution of W-1 (99 mg, 0.333 mmol), X-1 (77 mg, 0.399 mmol) andN,N-diisopropylethylamine (0.142 mL, 0.831 mmol) in THF (20 mL) wasstirred at reflux overnight. In order to complete the reaction, X-1 (236mg, 1.22 mmol) and N,N-diisopropylethylamine (0.63 mL, 3.7 mmol) wereadded portion wise over 2 days and the reaction mixture was stirred atreflux. Reaction mixture was allowed to come to RT and solvents wereremoved in vacuum. Residual brown oil (approx. 0.5 g) was dissolved inMeOH/CH₂Cl₂ and solids were filtered off. Preparative TLC(Heptane/Diethylether, 4:1 [3x], 9:1 [3x]) afforded 80 mg of a colorlessoil. Material was dissolved in DIPE and heptane was added. Removal ofsolvents in vacuum afforded compound 21 as a colorless solid (70 mg,56%).

Synthesis of Final Compound 25:

A solution of J-1 (100 mg, 0.29 mmol), trimethylacethyl chloride (35.5μL, 0.29 mmol), NEt₃ (40 μL, 0.29 mmol) in CH₂Cl₂ (4 mL) was stirredovernight at RT. The mixture was poured into an aqueous solution ofNaHCO₃ and extracted with CH₂Cl₂. Combined organic layers were dried,filtered and concentrated to give 120 mg. The crude was purified bycolumn chromatography (Normal phase on stability Silica (5 μm 150×30.0mm), mobile phase gradient from 0% NH₄OH, 100% DCM, 0% MeOH to 0.6%NH₄OH, 94% DCM, 6% MeOH). The solid was crystallized in diisopropyletherand dried under vacuum pressure at 70° C. to give compound 25 (81 mg,65%).

Synthesis of Final Compound 26:

Under nitrogen, oxalyl chloride (0.22 mL, 2.55 mmoles) was added to asuspension of S-1 in CH₂Cl₂ (50 mL). DMF (0.02 mL) was added drop wise(exothermic) and the reaction mixture was stirred at RT for 3 h.Solvents were removed under vacuum. The crude material Y-1 was useddirectly in the next step.

4-phenyl piperidine (0.089 g, 0.549 mmoles) was added to a suspension ofY-1 (0.099 g, 0.366 mmol) in THF (8 mL). Upon addition, solids dissolvedand color turned from brown-yellow to purple. N,N-diisopropylethylamine(0.188 mL, 1.098 mmol) was added and reaction mixture was stirred atreflux overnight. Water and EtOAc were added. Aqueous layer wasextracted with EtOAc. Combined organic extracts were dried with Na₂SO₄and solvents were removed under vacuum. The crude was purified by flashchromatography (CH₂Cl₂, 2% MeOH) to afford intermediate Z-1 as a yellowoil (66 mg, 46%).

A suspension of Z-1 (0.066 g, 0.167 mmol), 2-methoxyphenylboronic acid(0.038 g, 0.25 mmol) and sodium carbonate (0.060 g, 0.566 mmol) in DME(8 mL)/H₂O (2 mL) was flushed with argon for 5 min.Trans-BIS(Triphenylphosphine)palladium(II) chloride (6 mg, 8.6 μmol) wasadded and the suspension was flushed with argon for 5 min. Reactionmixture (suspension) was stirred at 60° C. under argon for 2 h. H₂O andEtOAc were added. Solids were filtered off. Layers were separated.Aqueous layer was extracted with EtOAc. Combined organic layers werewashed with brine and dried with Na₂SO₄. Solvents were removed undervacuum. The material was dissolved in CH₂Cl₂. Water was added and themixture was stirred vigorously overnight. Layers were separated. Aqueouslayer was extracted with CH₂Cl₂. Combined organic extracts were driedwith Na₂SO₄. Solvents were removed under vacuum. Material wascoevaporated with CH₂Cl₂. Et₂O was added to the yellow oil. The materialsolidified. The suspension was stirred in Et₂O overnight. The solid wasfiltered off, washed with Et₂O and H₂O and dried to give final compound26 (31%).

Synthesis of Final Compound 49:

J-1 (100 mg, 0.289 mmol), K₂CO₃ (80 mg, 0.57 mmol), propargyl bromide(solution 80% WT in toluene, 39 μL, 0.35 mmol) in CH₃CN (4 mL) werestirred at RT overnight. H₂O and CH₂Cl₂ were added, organic phase wasdecanted, dried off over MgSO₄ powder, filtered and solvent wasevaporated. The crude compound was purified by column chromatographyover silica-gel column (15-40 μm, 30 g) in CH₂Cl₂/MeOH/NH₄OH 97/3/0.5 togive 20 mg of compound 49 after crystallization inCH₃CN/Diisopropylether (18%).

Synthesis of Final Compound 55:

J-1 (200 mg, 0.58 mmol), trifluoroacetic anhydride (177 μL, 1.27 mmol),NEt₃ (642 μL, 4.62 mmol) in CH₂Cl₂ (4 mL) were stirred at RT for 12 h.The mixture was poured into an aqueous solution of NaHCO₃ and extractedwith CH₂Cl₂. Combined organic layers were dried, filtered andconcentrated to give 248 mg of intermediate Z-1. The crude compound wasused directly in the next step.

Under a N₂ flow, at −70° C., Et₂O (5 mL) was added to AlCl₃ (97 mg, 0.73mmol) then the mixture was stirred at 0° C. for 10 min. LiAlH₄ (1.12 mL,2.24 mmol) was added drop wise at 0° C. and the mixture was stirred at0° C. for 10 min. Z-1 (248 mg, 0.56 mmol) in THF (5 mL) was added dropwise and the mixture was stirred at 0° C. for 1 h. The reaction wasquenched with ice and EtOAc was added. The layers were decanted. Theorganic layer was washed with water, dried over MgSO₄, filtered and thesolvent was evaporated. The crude was purified by column chromatographyover silica gel (15-40 μm, 30 g) in CH₂Cl₂/MeOH/NH₄OH 98/2/0.1. Thecompound was then was purified by achiral Super critical fluidchromatography on 2-ETHYLPYRIDINE 6 μm 150×21.2 mm (mobile phase 92%CO₂, 8% MeOH) to give compound 55 (45 mg, 19%).

Synthesis of Final Compound 56:

To a solution of J-1 (250 mg, 0.72 mmol) in dichloromethane (3.6 mL) wasadded, at room temperature, 2,2-difluoroethyl triflate (230 mg, 1.08mmol) followed by triethylamine (0.36 mL, 2.16 mmol, 3 eq). The reactionmixture was then stirred at 50° C. for 16 hours and treated with water(5 mL). The aqueous crude mixture was extracted with dichloromethane(3×10 mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated in vacuum (300 mg). The crude compound wasthen purified on silica gel using ethyl acetate (100%) to afford thedesired compound 56 as a white solid (200 mg, 67% yield).

Synthesis of Final Compound 57:

To a solution of J-1 (250 mg, 0.72 mmol) in dichloromethane (3.6 mL) wasadded, at room temperature, A-2 (247 mg, 1.08 mmol) followed bytriethylamine (0.36 mL, 2.16 mmol). The reaction mixture was thenstirred at 50° C. for 16 hours and treated with water (5 mL). Theaqueous crude mixture was extracted with dichloromethane (3×10 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuum (650 mg). The crude compound was then purified onsilica gel using ethyl acetate/dichloromethane: 70/30 to afford thedesired compound 57 as a white solid (260 mg, 84% yield).

Synthesis of Final Compound 58:

To a solution of Q-1 (200 mg, 0.58 mmol) in dichloromethane (3 mL) wasadded, at room temperature, 2,2,2-trifluoroethyl triflate (0.13 mL, 0.88mmol) followed by triethylamine (0.24 mL, 1.76 mmol). The reactionmixture was then stirred at reflux for 2 hours. After 80% consumption ofQ-1 (monitoring by LCMS), the reaction mixture was treated with water (5mL). The aqueous crude mixture was extracted with dichloromethane (3×10mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated in vacuum (185 mg). The crude compound wasthen purified on silica gel using ethyl acetate/petroleum ether 50/50 toafford the desired compound 58 as a white solid (100 mg, 40% yield).

Synthesis of Final Compound 64:

To a stirred solution of N-1 (800 mg, 2.0 mmol) in acetonitrile (8 mL)was added, at room temperature 2,2,2-trifluoroacetimidamidehydrochloride B-2 (620 mg, 4.1 mmol) followed by DBU (0.93 mL, 6.2mmol). The reaction mixture was then heated in a sealed tube at 110° C.for 38 hours. After 54% consumption of N-1 (monitoring by LCMS), thereaction mixture was allowed to cool to room temperature, diluted withdichloromethane (30 mL) and treated with water (30 mL). The aqueouscrude mixture was extracted with dichloromethane (3×30 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedin vacuum. The crude compound was then purified on silica gel usingpetroleum ether/ethyl acetate 70/30 to afford the desired intermediateC-2 as a light yellow solid (315 mg, 35% yield).

To a solution of C-2 (465 mg, 1.08 mmol) in dichloromethane (5 mL),trifluoroacetic acid (1 mL) was added at room temperature. The reactionmixture was then stirred at room temperature for 5 hours. After completeconsumption of C-2 (monitoring by TLC), the reaction mixture wasconcentrated in vacuum to get a residue that was taken up indichloromethane (30 mL) and treated with a saturated aqueous solution ofpotassium carbonate (30 mL). The aqueous crude mixture was extractedwith dichloromethane (3×30 mL). The combined organic layers were driedover sodium sulfate, filtered and concentrated in vacuum to afford thedesired intermediate D-2 as a light yellow solid (340 mg, 94% yield)which was used in the next step without any further purification.

To a solution of D-2 (340 mg, 1.02 mmol) in dichloroethane (13 mL),acetic acid (0.19 mL, 4.59 mmol) was added, at room temperature,followed by 2,2-dimethylpropanal (0.33 mL, 3.07 mmol). The reactionmixture was then stirred at room temperature for 5 hours before addingsodium triacetoxyborohydride (867 mg, 4.08 mmol). Reaction mixture wasstirred at room temperature for 48 hours and then diluted withdichloromethane (30 mL) and treated with a saturated solution of sodiumbicarbonate (30 mL). The aqueous layer was extracted withdichloromethane (3×40 mL). The combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuum (400 mg). The crudecompound was then purified on silica gel usingdichloromethane/methanol/ammonium hydroxide solution (33% in H₂O):99/1/0.1 to afford the desired compound 64 as a white solid (260 mg, 63%yield).

Synthesis of Final Compound 70:

To a stirred solution of J-1 (800 mg, 2.3 mmol) in acetonitrile (9.2 mL)and dichloromethane (4.8 mL) was added, at room temperature,chloroacetone E-2 (0.27 mL, 3.45 mmol) followed by potassium carbonate(0.64 g, 4.6 mmol). The reaction mixture was then heated at reflux for 8hours. The reaction mixture was allowed to cool to room temperaturediluted with dichloromethane (30 mL) and treated with water (30 mL). Theaqueous crude mixture was extracted with dichloromethane (2×30 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuum to afford the desired intermediate F-2 as a redoil (930 mg, 100% yield) which was used in the next step without anyfurther purification.

To a solution of F-2 (930 mg, 2.3 mmol) in dichloromethane (115 mL),diethyl amino sulfur trifluoride (DAST) (0.57 mL, 6.9 mmol) was addeddrop wise, at −78° C. The reaction mixture was then stirred at roomtemperature for 16 hours. The reaction mixture was diluted withdichloromethane (50 mL) and treated with a saturated aqueous solution ofsodium carbonate (50 mL), at 0° C. The aqueous crude mixture wasextracted with dichloromethane (2×50 mL). The combined organic layerswere dried over sodium sulfate, filtered and concentrated in vacuum. Thecrude compound was first purified on silica gel usingdichloromethane/methanol/ammonium hydroxide solution (33% in H₂O):99/1/0.1, then another purification was done usingdichloro-methane/ethyl acetate: 80/20. The residue was finallytriturated with pentane to afford the desired compound 70 as a browngummy solid (60 mg, 6%).

Synthesis of Final Compound 89:

To a mixture of intermediate G-2 (0.15 g, 0.38 mmol) in dichloromethane(20 mL) was added tri-ethylamine (0.12 g, 1.14 mmol) followed bycompound 1-2 (0.053 g, 0.38 mmol) at 0° C. The reaction mixture wasstirred at 25° C. under N₂ for 15 hours. The mixture was diluted withdichloromethane and washed with saturated aqueous sodium bicarbonate.The aqueous layer is back extracted with dichloromethane. The combinedorganic layers were washed with brine, dried and evaporated to giveintermediate I-2 (0.16 g, 90%).

To a solution of intermediate I-2 (0.16 g, 0.35 mmol) in dichloromethane(15 mL) was added m-CPBA (0.066 g, 0.38 mmol) portion wise at 0° C. Themixture was stirred at 15° C. for 20 hours. The solid was precipitatedout and filtered through a pad of celite and washed withdichloromethane. The filtrate was purified by high-performance liquidchromatography to give compound 89 (16 mg, 12%).

Synthesis of Final Compound 91:

Triethylsilyl acetylene (38 mg, 0.27 mmol) was added to a solution ofcompound 90 (0.12 g, 0.18 mmol), Pd(PPh₃)₄ (21 mg, 0.018 mmol),tri-ethylamine (0.22 g, 2.16 mmol) and Copper(I) iodide (3 mg, 0.011mmol) in DMF (3 mL) at room temperature under N₂ in a microwave vessel.The vessel was capped and irradiated at 110° C. for 40 minutes. Thereaction mixture was concentrated under vacuum and the residue wasdiluted with ethyl acetate (30 mL) and water (10 mL). The organic layerwas separated, dried over Na₂SO₄ and the solvent was removed underreduced pressure. The crude product was dried under vacuum and useddirectly in the next step. 0.15 g of crude intermediate J-2 wasobtained.

Intermediate J2 (crude, 0.18 mmol) in dry THF (35 mL) was added to asolution of tetra-butylammonium fluoride (1 M in THF, 7.5 mL). Themixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated and the crude product was directly purified bybasic preparative high-performance liquid chromatography (column: C18,eluent: CH₃CN/H₂O 97/3, 0.05% NH₃.H₂O). The desired fraction wascollected and the solvent was removed under reduced pressure. Theproduct was dried under vacuum to give compound 91 (10 mg, 13%).

Mass LCMS Ret Exact Found Time, Synthesis # STRUCTURE Mass [M + H]Method method MP (° C.)  1

456.20 457 1.53 B5501 Intermediate J1 Final compound 9  2

414.24 415 1.46 B5501 Intermediate J1 Final compound 9  3

454.22 455 4.23 MERC22 Intermediate J1 Final compound 9 111-114  4

442.18 443 4.3 V3007V3001 Intermediate J1 Final compound 6 135 (K)  5

486.18 487 4.23 MERC22 Intermediate J1 Final compound 9 227-228  6

416.26 417 5.45 V3007V3001 Intermediate J1 Final compound 6 118 (K)  7

422.21 423 1.43 B5501 Intermediate J1 Final compound 9  8

436.23 437 4.47 MERC20 Intermediate J1 Final compound 9 149-151  9

486.18 487 4.29 MERC22 Intermediate J1 Final compound 9 119-123 10

452.22 453 4.17 MERC22 Intermediate J1 Final compound 9 142-146 11

402.24 403 4.3 MERC22 Intermediate J1 Final compound 6 105-106 12

386.21 387 4.06 MERC22 Intermediate J1 Final compound 12 153-156 13

470.19 469 (M − H) 4.42 MERC22 Intermediate J1 Final compound 9 180-18114

438.22 439 4.38 MERC22 Intermediate J1 Final compound 9 195-196 15

400.26 401 4.62 MERC22 Intermediate J1 Final compound 6 123-127 16

436.23 437 4.63 V3007V3001 Intermediate J1 Final compound 9 174 (K) 17

442.27 443 4.86 V3007V3001 Intermediate J1 Final compound 6 130 (K) 18

426.21 427 4.23 V3007V3001 Intermediate J1 Final compound 6 120 (K) 19

442.18 443 4.65 V3007V3001 Intermediate J1 Final compound 6 130 (K) 20

494.23 495 4.1 V3007V3001 Intermediate J1 Final compound 20 21

417.25 418 4.63 MERC22 Intermediate XI Final compound 21 117-120 22

509.24 510 3.19 MERC26 Intermediate XI Final compound 21 106-108 23

486.18 487 4.16 MERC27 Intermediate J1 Final compound 9 165-166 24

416.26 417 4.89 MERC27 Intermediate J1 Final compound 6 222-224 25

430.24 431 4.05 V3007V3001 Intermediate J1 Final compound 25 165 (K) 26

422.21 423 4.4 MERC28 Final compound 26 157-159 27

494.23 495 3.77 MERC28 Intermediate J1 Final compound 20 138-140 28

504.21 505 5.08 V3007V3001 Intermediate J1 Final compound 6 156 (K) 29

454.22 455 4.67 V3007V3001 Intermediate J1 Final compound 6 152 (K) 30

431.27 432 4.86 MERC27 Final compound 26 137-138 31

461.22 462 4.5 V3007V3001 Intermediate J1 Final compound 6 140 (K) 32

472.21 473 4.82 V3007V3001 Intermediate J1 Final compound 6 138 (K) 33

450.24 451 4.86 V3007V3001 Intermediate J1 Final compound 6 160 (K) 34

461.22 462 4.5 V3007V3001 Intermediate J1 Final compound 6 168 (K) 35

450.24 451 4.77 V3007V3001 Intermediate J1 Final compound 6 141 (K) 36

416.26 417 4.95 MERC25 Intermediate J1 Final compound 6 154-156 37

429.29 430 5.22 MERC30 Intermediate J1 Final compound 6 140-142 38

400.26 401 5.6 MERC27 Intermediate J1 Final compound 6 170-171 39

420.21 421 5.48 MERC27 Intermediate J1 Final compound 6 119-121 40

454.23 455 5.32 MERC27 Intermediate J1 Final compound 6 112-114 41

454.22 455 4.74 V3007V3001 Intermediate J1 Final compound 6 139 (K) 42

461.22 462 4.57 V3007V3001 Intermediate J1 Final compound 6 158 (K) 43

472.21 473 4.87 V3007V3001 Intermediate J1 Final compound 6 158 (K) 44

470.19 471 5.09 V3007V3001 Intermediate J1 Final compound 6 131 (K) 45

470.19 471 5.15 V3007V3001 Intermediate J1 Final compound 6 133 (K) 46

504.21 505 5.38 V3007V3001 Intermediate J1 Final compound 6 144 (K) 47

472.21 473 4.99 V3007V3001 Intermediate J1 Final compound 6 184 (K) 48

472.21 473 4.99 V3007V3001 Intermediate J1 Final compound 6 181 (K) 49

384.20 385 3.92 V3007V3001 Intermediate J1 Final compound 49 160 (K) 50

400.26 401 5.91 V3007V3001 Intermediate J1 Final compound 6 208 (K) 51

370.25 371 6.08 B5301 — 52

386.22 387 6.65 B5301 — 53

382.27 383 5.85 B5301 — 54

411.24 412 4.7 V3007V3001 Intermediate Q1 Final compound 6 155 (K) 55

428.18 429 4.49 V3007V3001 Intermediate J1 Final compound 55 56

410.19 411 11.52 NOVA1 Intermediate J1 Final compound 56 123 (B) 57

427.24 428 11.77 NOVA1 Intermediate J1 Final compound 57 117 (B) 58

423.17 424 11.73 NOVA1 Intermediate Q1 Final compound 58 168-172 (B) 59

423.17 424 12.3 NOVA1 Intermediate Q1 Final compound 58 163-164 (B) 60

423.17 424 12.46 NOVA1 Intermediate Q1 Final compound 58 52-92 (B) 61

411.24 412 11.74 NOVA1 Intermediate Q1 Final compound 6 65-153 (B) 62

411.24 412 11.98 NOVA1 Intermediate Q1 Final compound 6 57-113 (B) 63

374.25 375 13.38 NOVA1 Final compound 64 125-126 (B) 64

402.20 403 13.63 NOVA1 Final compound 64 114-116 (B) 65

435.24 436 14.25 NOVA1 Intermediate Q1 Final compound 6 247-249 (B) 66

428.24 429 14.62 NOVA1 Intermediate Q1 Final compound 6 154-158 (B) 67

441.25 442 14.14 NOVA1 Intermediate Q1 Final compound 6 144-145 (B) 68

412.24 413 13.13 NOVA1 Intermediate Q1 Final compound 6 163-170 (B) 69

411.24 412 11.88 NOVA1 Intermediate Q1 Final compound 6 148-150 (B) 70

424.21 425 11.7 NOVA1 Intermediate J1 Final compound 70 71

445.18 446 4.95 WUXI2 Intermediate J1 Final compound 58 72

425.22 426 3.7 WUXI1 Intermediate Q1 Final compound 6 73

386.22 387 2.85 WUXI2 Intermediate XI Final compound 21 74

412.24 413 2.7 WUXI2 Intermediate X1 Final compound 21 155-164 (WRS-2A)75

422.22 423 3.82 WUXI1 Intermediate Q1 Final compound 57 79-87 (WRS-2A)76

440.16 441 4.64 WUXI2 Intermediate Q1 Final compound 58 157-158 (WRS-2A)77

442.22 443 6.72 WUXI1 Intermediate Q1 Final compound 25 75-80 (WRS-2A)78

444.23 445 4.04 WUXI2 Intermediate J1 Final compound 57 119 (WRS-2A) 79

458.19 459 4.5 WUXI2 Intermediate J1 Final compound 58 80

439.22 440 3.91 WUXI2 Intermediate Q1 Final compound 57 171 (WRS-2A) 81

457.25 458 3.47 WUXI14 Intermediate J1 Final compound 57 82

423.22 424 4.23 WUXI1 Intermediate Q1 Final compound 57 182 (WRS-2A) 83

452.18 453 4.69 WUXI2 Intermediate J1 Final compound 58 180-182 (WRS-2A)84

447.17 448 4.45 WUXI2 Intermediate Q1 Final compound 58 249-251 (WRS-2A)85

452.23 453 4.85 WUXI1 Intermediate Q1 Final compound 57 165 (WRS-2A) 86

451.24 452 3.94 WUXI2 Intermediate J1 Final compound 57 207 (WRS-2A) 87

499.20 500 4.62 WUXI1 Intermediate Q1 Final compound 57 101-122 (WRS-2A)88

504.15 505 4.25 WUXI2 Intermediate J1 Final compound 57 89

478.18 479 5.1 WUXI2 Intermediate Q1 Final compound 89 90

493.17 494 3.27 WUXI3 Intermediate J1 Final compound 6 91

439.26 440 4.41 WUXI2 Final compound 91 92

450.24 451 4.27 WUXI2 Final compound 91 93

451.19 452 5.18 WUXI2 Final compound 91Analytical Methods.All Compounds were Characterized by LC-MS. The Following LC-MS Methodswere Used:General Procedure NOVA (for Methods NOVAx)

The HPLC measurement was performed using an HPLC 1100/1200 (Agilent)system comprising a quaternary pump with degasser, an autosampler, adiode-array detector (DAD) and a column as specified in the respectivemethods below, the column is held at a room temperature. The MS detector(MS-Agilent simple quadripole) was configured with an electrospray-APCIionization source. Nitrogen was used as the nebulizer gas. Dataacquisition was performed with a Chemstation data system.

Method NOVA1:

In addition to the general procedure NOVA: Reversed phase HPLC wascarried out on a Nucleosil C18 column (3 μm, 3×150 mm) with a flow rateof 0.42 ml/min. Two mobile phases (mobile phase A: Water TFA 0.1%;mobile phase B: 100% acetonitrile) were employed to run a gradientcondition from 98% A for 3 minutes, to 100% B in 12 minutes, 100% B for5 minutes, then back to 98% A in 2 minutes, and reequilibrated with 98%A for 6 minutes. An injection volume of 2 μl was used. The capillaryvoltage was 2 kV, the corona discharge was held at 1 μA and the sourcetemperature was maintained at 250° C. A variable voltage was used forthe fragmentor. Mass spectra were acquired in electrospray ionizationand APCI in positive mode, by scanning from 100 to 1100 amu.

Method NOVA2:

In addition to the general procedure NOVA: Reversed phase HPLC wascarried out on a Agilent Eclipse C18 column (5 μm, 4.6×150 mm) with aflow rate of 1 ml/min. Two mobile phases (mobile phase A: Water TFA0.1%; mobile phase B: 100% acetonitrile) were employed to run a gradientcondition from 98% A for 3 minutes, to 100% B in 12 minutes, 100% B for5 minutes, then back to 98% A in 2 minutes, and reequilibrated with 98%A for 6 minutes. An injection volume of 2 μl was used. The capillaryvoltage was 2 kV, the corona discharge was held at 1 μA and the sourcetemperature was maintained at 250° C. A variable voltage was used forthe fragmentor. Mass spectra were acquired in electrospray ionizationand APCI in positive mode, by scanning from 80 to 1000 amu.

Method NOVA3:

In addition to the general procedure NOVA: Reversed phase HPLC wascarried out on a Phenomenex Gemini C18 column (3 μm, 3×30 mm) with aflow rate of 0.7 ml/min. Two mobile phases (mobile phase A: Water TFA0.1%; mobile phase B: 100% acetonitrile) were employed to run a gradientcondition from 98% A to 100% B in 2 minutes, 100% B for 0.5 minutes,then back to 98% A in 0.1 minutes, and reequilibrated with 98% A for 2.4minutes. An injection volume of 2 μl was used. The capillary voltage was2 kV, the corona discharge was held at 1 μA and the source temperaturewas maintained at 250° C. A variable voltage was used for thefragmentor. Mass spectra were acquired in electrospray ionization andAPCI in positive mode, by scanning from 80 to 1000 amu.

General Procedure B (for Methods Bxxxx)

The HPLC measurement was performed using an HPLC Alliance 2695 (Waters)system comprising a quaternary pump with degasser, an autosampler, adiode-array detector (DAD), a CLND detector (Antek) and a column asspecified in the respective methods below, the column is held at 40° C.The MS detector (ZQ-Waters simple quadripole) was configured with anelectrospray ionization source. Nitrogen was used as the nebulizer gas.Data acquisition was performed with a Masslynx-Openlynx data system.

Method B5301:

In addition to the general procedure B: Reversed phase HPLC was carriedout on a X-terra MS C18 column (3.5 μm, 4.6×100 mm) with a flow rate of1.5 ml/min. Two mobile phases (mobile phase A: Water with 0.1% formicacid: 95/Methanol: 5%; mobile phase B: 100% Methanol) were employed torun a gradient condition from 100% A to 5% A/95% B in 12 minutes, andback to 100% A in 1 minutes. An injection volume of 10 μl was used. Thecone voltage was 30V for both positive and negative ionization. Massspectra were acquired in electrospray ionization and APCI in positivemode, by scanning from 100 to 1500 amu.

Method B5501:

In addition to the general procedure B: Reversed phase HPLC was carriedout on a BEH C18 column (1.7 μm, 2.1×50 mm) with a flow rate of 0.7ml/min. Two mobile phases (mobile phase A: Methanol, B: Ammonium acetate10 mM in water: 90%/Acetonitrile: 10%) were employed to run a gradientcondition from 5% A/95% B to 95% A/5% B in 1.3 minutes held for 0.2minutes, and back to 5% A/95% B in 0.2 minutes, held for 0.3 minutes. Aninjection volume of 0.75 ml was used. The cone voltage was 30V for bothpositive and negative ionization. Mass spectra were acquired inelectrospray ionization, by scanning from 160 to 1000 amu.

General Procedure VDR2 (for Methods V300xV30xx)

The LC measurement was performed using a UPLC (Ultra Performance LiquidChromatography) Acquity (Waters) system comprising a binary pump withdegasser, an autosampler, a diode-array detector (DAD) and a column asspecified in the respective methods below, the column is hold at atemperature of 40° C. Flow from the column was brought to a MS detector.The MS detector was configured with an electrospray ionization source.The capillary needle voltage was 3 kV and the source temperature wasmaintained at 130° C. on the Quattro (triple quadrupole massspectrometer from Waters). Nitrogen was used as the nebulizer gas. Dataacquisition was performed with a Waters-Micromass MassLynx-Openlynx datasystem.

Method V3007V3001

In addition to the general procedure VDR2: Reversed phase UPLC wascarried out on a Waters Acquity BEH (bridged ethylsiloxane/silicahybrid) C18 column (1.7 μm, 2.1×100 mm) with a flow rate of 0.35 ml/min.Two mobile phases (mobile phase A: 95% 7 mM ammonium acetate/5%acetonitrile; mobile phase B: 100% acetonitrile) were employed to run agradient condition from 90% A and 10% B (hold for 0.5 minutes) to 8% Aand 92% B in 3.5 minutes, hold for 2 min and back to the initialconditions in 0.5 min, hold for 1.5 minutes. An injection volume of 2 mlwas used. Cone voltage was 20 V for positive and negative ionizationmode. Mass spectra were acquired by scanning from 100 to 1000 in 0.2seconds using an interscan delay of 0.1 seconds.

General Procedure Wuxi (for Methods WUXIx)

The HPLC measurement was performed using an HPLC 1100/1200 (Agilent)system comprising a quaternary pump with degasser, an autosampler, adiode-array detector (DAD) and a column as specified in the respectivemethods below, the column is held at 50° C. The MS detector (AgilentG1946C or 6110) was configured with an Electrospray or an APCIionization source. Nitrogen was used as the nebulizer gas. Dataacquisition was performed with a Agilent Chemstation data system.

Method WUXI1:

In addition to the general procedure WUXI: Reversed phase HPLC wascarried out on a YMC-PACK ODS-AQ C18 column (5 μm, 2×50 mm) with a flowrate of 0.8 ml/min. Two mobile phases (mobile phase A: Water with 0.1%trifluoro-acetic acid; mobile phase B: acetonitrile with 0.05%trifluoro-acetic acid) were employed to run a gradient conditionstarting from 100% A held for 1 minutes, to 40% A/60% B in 4 minutes,held for 2.5 min, then back to 100% A in 0.5 minutes. An injectionvolume of 2 μl was used. The capillary voltage was 2.5 kV for positiveionization mode and 3 kV for negative ionization mode, the coronadischarge was held at 4 μA if APCI and the source temperature wasmaintained at 200° C. Fragmentation voltage was 70V. Mass spectra wereacquired in electrospray ionization or APCI in positive mode, byscanning from 100 to 1000 amu.

Method WUXI2:

In addition to the general procedure WUXI: Reversed phase HPLC wascarried out on a YMC-PACK ODS-AQ C18 column (5 μm, 2×50 mm) with a flowrate of 0.8 ml/min. Two mobile phases (mobile phase A: Water with 0.1%trifluoro-acetic acid; mobile phase B: acetonitrile with 0.05%trifluoro-acetic acid) were employed to run a gradient conditionstarting from 90% A/10% B held for 0.8 minutes, to 20% A/80% B in 3.7minutes, held for 3 min, then back to initial conditions in 0.5 minutes.The capillary voltage was 2.5 kV for positive ionization mode and 3 kVfor negative ionization mode, the corona discharge was held at 4 μA ifAPCI and the source temperature was maintained at 200° C. Fragmentationvoltage was 70V. Mass spectra were acquired in electrospray ionizationor APCI in positive mode, by scanning from 100 to 1000 amu.

Method WUXI3:

In addition to the general procedure WUXI: Reversed phase HPLC wascarried out on a YMC-PACK ODS-AQ C18 column (5 μm, 2×50 mm) with a flowrate of 0.8 ml/min. Two mobile phases (mobile phase A: Water with 0.1%trifluoro-acetic acid; mobile phase B: acetonitrile with 0.05%trifluoro-acetic acid) were employed to run a gradient conditionstarting from 70% A/30% B held for 0.8 minutes, to 10% A/90% B in 3.2minutes, held for 3.5 min, then back to initial conditions in 0.5minutes. The capillary voltage was 2.5 kV for positive ionization modeand 3 kV for negative ionization mode, the corona discharge was held at4 μA if APCI and the source temperature was maintained at 200° C.Fragmentation voltage was 70V. Mass spectra were acquired inelectrospray ionization or APCI in positive mode, by scanning from 100to 1000 amu.

Method WUXI4:

In addition to the general procedure WUXI: Reversed phase HPLC wascarried out on a Agilent TC-C18 column (5 μm, 2.1×50 mm) with a flowrate of 0.8 ml/min. Two mobile phases (mobile phase A: Water with 0.1%trifluoro-acetic acid; mobile phase B: acetonitrile with 0.05%trifluoro-acetic acid) were employed to run a gradient conditionstarting from 90% A/10% B held for 0.8 minutes, to 20% A/80% B in 3.7minutes, held for 3 min, then back to initial conditions in 2 minutes.The capillary voltage was 2.5 kV for positive ionization mode and 3 kVfor negative ionization mode, the corona discharge was held at 4 μA ifAPCI and the source temperature was maintained at 200° C. Fragmentationvoltage was 70V. Mass spectra were acquired in electrospray ionizationor APCI in positive mode, by scanning from 100 to 1000 amu.

General Procedure Mercachem (for Methods MERCx)

The HPLC measurement was performed using an HPLC 1100-SL or 1200-SL(Agilent) system comprising a quaternary pump with degasser, anautosampler, a diode-array detector (DAD) and a column as specified inthe respective methods below. The MS detector (Agilent MSD-SL) wasconfigured with an Electrospray ionization source. Data acquisition wasperformed with a Agilent Chemstation data system.

Method MERC20:

In addition to the general procedure MERC: Reversed phase HPLC wascarried out on a Waters X-Bridge C18 column (3.5 μm, 2.1×50 mm) held at25° C. with a flow rate of 0.8 ml/min. Two mobile phases (mobile phaseA: Acetonitrile with 10 mM ammonia; mobile phase B: Water with 10 mMammonia) were employed to run a gradient condition starting from 2% A to98% A/2% B in 3.5 minutes, held for 2.5 min. Mass spectra were acquiredin electrospray ionization in positive & negative mode, by scanning from220 to 800 amu.

Method MERC22:

In addition to the general procedure MERC: Reversed phase HPLC wascarried out on a Waters X-Bridge C18 column (3.5 μm, 2.1×50 mm) held at25° C. with a flow rate of 0.8 ml/min. Two mobile phases (mobile phaseA: 95% Methanol/5% 10 mM ammonium bicarbonate in Water; mobile phase B:10 mM ammonium bicarbonate in Water) were employed to run a gradientcondition starting from 10% A to 98% A/2% B in 2.5 minutes, held for 3.5min. Mass spectra were acquired in electrospray ionization in positive &negative mode, by scanning from 220 to 800 amu.

Method MERC25:

In addition to the general procedure MERC: Reversed phase HPLC wascarried out on a Gemini C18 column (3 μm, 2.1×50 mm) held at 25° C. witha flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: 95%Acetonitrile/5% 10 mM ammonium bicarbonate in Water; mobile phase B: 10mM ammonium bicarbonate in Water) were employed to run a gradientcondition starting from 2% A to 98% A/2% B in 3.5 minutes, held for 2.5min. Mass spectra were acquired in electrospray ionization in positive &negative mode, by scanning from 100 to 800 amu.

Method MERC26:

In addition to the general procedure MERC: Reversed phase HPLC wascarried out on a Waters X-Bridge C18 column (3.5 μm, 2.1×50 mm) held at25° C. with a flow rate of 0.8 ml/min. Two mobile phases (mobile phaseA: 0.1% formic acid in Acetonitrile; mobile phase B: 0.1% formic acid inWater) were employed to run a gradient condition starting from 2% A to98% A/2% B in 3.5 minutes, held for 2.5 min. Mass spectra were acquiredin electrospray ionization in positive & negative mode, by scanning from100 to 800 amu.

Method MERC27:

In addition to the general procedure MERC: Reversed phase HPLC wascarried out on a Waters X-Bridge C18 column (3.5 μm, 2.1×50 mm) held at25° C. with a flow rate of 0.8 ml/min. Two mobile phases (mobile phaseA: 95% Acetonitrile/5% 10 mM ammonium bicarbonate in Water; mobile phaseB: 10 mM ammonium bicarbonate in Water) were employed to run a gradientcondition starting from 2% A to 98% A/2% B in 3.5 minutes, held for 4.5min. Mass spectra were acquired in electrospray ionization in positive &negative mode, by scanning from 100 to 800 amu.

Method MERC28:

In addition to the general procedure MERC: Reversed phase HPLC wascarried out on a Waters X-Bridge C18 column (3.5 μm, 2.1×50 mm) held at25° C. with a flow rate of 0.8 ml/min. Two mobile phases (mobile phaseA: 95% Acetonitrile/5% 10 mM ammonium bicarbonate in Water; mobile phaseB: 10 mM ammonium bicarbonate in Water) were employed to run a gradientcondition starting from 2% A to 98% A/2% B in 3.5 minutes, held for 2.5min. Mass spectra were acquired in electrospray ionization in positive &negative mode, by scanning from 100 to 800 amu.

Method MERC30:

In addition to the general procedure MERC: Reversed phase HPLC wascarried out on a Gemini C18 column (3 μm, 2.1×50 mm) held at 25° C. witha flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: 95%Acetonitrile/5% 10 mM ammonium bicarbonate in Water; mobile phase B: 10mM ammonium bicarbonate in Water) were employed to run a gradientcondition starting from 2% A to 98% A/2% B in 3.5 minutes, held for 4.5min. Mass spectra were acquired in electrospray ionization in positive &negative mode, by scanning from 100 to 800 amu.

H¹ NMR Analysis of Final Compounds:

Compound 6

¹H NMR (500 MHz, DMSO-d₆) d 8.81 (d, J=5.67 Hz, 2H), 8.77 (s, 1H), 8.31(d, J=5.67 Hz, 2H), 7.46 (t, J=7.88 Hz, 1H), 7.07 (d, J=7.88 Hz, 1H),6.98-7.04 (m, 2H), 3.81 (s, 3H), 2.79-2.89 (m, 3H), 1.96-2.15 (m, 6H),1.66 (d, J=11.98 Hz, 2H), 0.86 (s, 9H)

Compound 55

¹H NMR (500 MHz, DMSO-d₆) δ 8.74-8.85 (m, 3H), 8.33 (d, J=4.73 Hz, 2H),7.46 (t, J=7.88 Hz, 1H), 6.97-7.11 (m, 3H), 3.82 (s, 3H), 3.16 (q,J=9.98 Hz, 2H), 2.99 (d, J=11.03 Hz, 2H), 2.90 (t, J=11.03 Hz, 1H), 2.27(t, J=11.66 Hz, 2H), 2.02 (q, J=11.66 Hz, 2H), 1.72 (d, J=11.66 Hz, 2H)

Compound 58

¹H NMR (400 MHz, CHLOROFORM-d) δ 8.86 (d, J=5.31 Hz, 2H), 8.67 (s, 1H),8.44 (d, J=5.31 Hz, 2H), 7.86 (d, J=7.83 Hz, 1H), 7.67-7.76 (m, 2H),7.64 (d, J=7.83 Hz, 1H), 3.02-3.17 (m, 4H), 2.80 (s, 1H), 2.37-2.47 (m,2H), 2.22-2.37 (m, 2H), 1.75 (d, J=13.39 Hz, 2H)

Compound 70

¹H NMR (400 MHz, CHLOROFORM-d) δ 8.85 (d, J=6.06 Hz, 2H), 8.69 (s, 1H),8.41-8.46 (m, 2H), 7.48 (t, J=8.08 Hz, 1H), 7.07 (dd, J=2.02, 8.08 Hz,1H), 6.96 (d, J=7.33 Hz, 1H), 6.90 (s, 1H), 3.93 (s, 3H), 3.03-3.14 (m,2H), 2.90-3.01 (m, 1H), 2.73 (t, J=13.64 Hz, 2H), 2.18-2.32 (m, 4H),1.74 (s, 2H), 1.62 (br. s., 3H)

Compound 67

¹H NMR (400 MHz, CHLOROFORM-d) δ 9.31 (d, J=2.27 Hz, 1H), 8.60 (dd,J=2.27, 8.59 Hz, 1H), 8.43 (s, 1H), 7.69 (d, J=7.58 Hz, 1H), 7.53-7.60(m, 2H), 7.45-7.52 (m, 1H), 6.80 (d, J=8.59 Hz, 1H), 3.97 (s, 3H), 2.80(d, J=6.82 Hz, 2H), 2.57 (br. s., 1H), 2.01-2.16 (m, 4H), 1.96 (s, 2H),1.49-1.58 (m, 2H), 0.81 (s, 9H)

Compound 57

¹H NMR (400 MHz, DMSO-d₆) δ 8.76-8.85 (m, 3H), 8.29-8.37 (m, 2H),7.42-7.52 (m, 1H), 6.97-7.12 (m, 3H), 3.83 (s, 3H), 3.02 (d, J=11.12 Hz,2H), 2.89 (t, J=11.10 Hz, 1H), 2.44 (s, 2H), 2.14-2.27 (m, 2H),1.94-2.12 (m, 2H), 1.72 (d, J=12.63 Hz, 2H), 1.29 (s, 6H)

Compound 66

¹H NMR (400 MHz, CHLOROFORM-d) δ 8.62 (dd, J=5.81, 8.84 Hz, 2H), 8.57(s, 1H), 7.82 (d, J=7.58 Hz, 1H), 7.66-7.73 (m, 2H), 7.61 (s, 1H), 7.25(t, J=8.84 Hz, 2H), 2.94 (d, J=7.58 Hz, 2H), 2.60-2.78 (m, 1H),2.13-2.31 (m, 4H), 2.09 (s, 2H), 1.64 (d, J=8.34 Hz, 2H), 0.95 (s, 9H)

Compound 65

¹H NMR (400 MHz, CHLOROFORM-d) δ 8.73 (d, J=8.34 Hz, 2H), 8.63 (s, 1H),7.80-7.90 (m, 3H), 7.66-7.74 (m, 2H), 7.60-7.65 (m, 1H), 2.94 (d, J=6.57Hz, 2H), 2.65-2.79 (m, 1H), 2.14-2.30 (m, 4H), 2.09 (s, 2H), 1.65 (d,J=4.80 Hz, 2H), 0.95 (s, 9H)

Compound 71

¹H NMR (400 MHz, CHLOROFORM-d) δ 8.49-8.61 (m, 3H), 7.41 (t, J=8.03 Hz,1H), 7.17 (t, J=8.03 Hz, 2H), 7.00 (dd, J=2.01, 8.03 Hz, 1H), 6.90 (d,J=8.03 Hz, 1H), 6.81-6.86 (m, 1H), 3.87 (s, 3H), 2.84-3.11 (m, 5H),2.16-2.42 (m, 4H), 1.70 (d, J=13.05 Hz, 2H)

Compound 39

¹H NMR (400 MHz, DMSO-d₆) δ 8.73-8.90 (m, 3H), 8.32 (d, J=6.06 Hz, 2H),7.53-7.68 (m, 3H), 7.40-7.50 (m, 1H), 2.84 (d, J=11.12 Hz, 2H),2.68-2.79 (m, 1H), 1.92-2.17 (m, 6H), 1.66 (d, J=12.13 Hz, 2H), 0.86 (s,9H)

Compound 21

¹H NMR (400 MHz, DMSO-d₆) δ 8.69-8.79 (m, 2H), 8.36 (s, 1H), 8.19-8.28(m, 2H), 7.34-7.48 (m, 1H), 7.04-7.15 (m, 2H), 6.97 (dd, J=1.77, 8.34Hz, 1H), 3.81 (s, 3H), 3.36-3.40 (m, 3H), 2.46 (t, J=4.55 Hz, 3H), 2.04(s, 2H), 1.23 (br. s., 2H), 0.83 (s, 9H)

Compound 40

¹H NMR (400 MHz, DMSO-d₆) δ 8.75-8.96 (m, 3H), 8.33 (d, J=6.06 Hz, 2H),7.89 (br. s., 2H), 7.72-7.85 (m, 2H), 2.84 (d, J=9.35 Hz, 2H), 2.63-2.77(m, 1H), 1.93-2.17 (m, 6H), 1.56-1.78 (m, 2H), 0.85 (s, 9H)

The following six compounds/examples were also prepared in accordancewith the procedures described herein:

BIOLOGICAL EXAMPLES In Vitro Method for Testing Compounds forAntibacterial Activity Against Various Bacterial Strains

Preparation of Bacterial Suspensions for Susceptibility Testing

The following bacteria were used: Staphylococcus aureus ATCC 29213,methicillin-resistant Staphylococcus aureus (MRSA) ATCC 700788 andEscherichia coli ATCC 35218. The bacteria used in this study were grownovernight in flasks containing 100 ml Mueller-Hinton broth (Difco cat.nr. 0757-17) in sterile de-ionized water, with shaking, at 37° C. Stockswere store at −70° C. until use.

Bacteria were incubated on a tryptic soy agar plate containing 5% sheepblood (Becton Dickinson cat. nr. 254053) for 18-24 hours at 35° C. inaerobic conditions (first passage). For the second passage, freshMueller-Hinton broth is inoculated with 5-10 colonies and grownovernight at 35° C. until turbidity (reaching log-phase) in aerobicconditions is reached. The bacterial suspension is then adjusted to 0.5McFarland density and further diluted 1:100 in Mueller Hinton brothmedium. This is used as inoculum.

Antibacterial Susceptibility Testing: IC90 Determination

MIC assays were performed by the broth microdilution method in a 96-wellformat (flat-bottom microtitre plates) with a final volume of 0.1 mlMueller Hinton broth containing two-fold serial dilutions of compoundsand inoculated with 5×105 CFU/ml of bacteria (standard inoculum sizeaccording to CLSI guidelines). Inhibitors are typically varied over therange of 63 to 0.49 μM. The final DMSO concentration in the assay was1.25% (maximum tolerable DMSO concentration=6%). In the assays where theeffect of human serum on the activity of the compounds against S. aureuswas tested, human serum was added at a final concentration of 10%. Theplates were incubated at 35° C. for 16-20 hours. At the end ofincubation the bacterial growth was quantified fluorometrically. Forthis, resazurin was added to all wells and the plates were re-incubated.The incubation time is dependent on the type of bacteria. A change incolor from blue to pink indicated the growth of bacteria. Thefluorescence was read in computer-controlled fluorometer (FluoroskanAscent FL, Labsystems) at an excitation wavelength 540 nm and anemission wavelength of 590 nm. The % growth inhibition achieved by thecompounds was calculated according to standard methods. The IC90(expressed in μg/ml) was defined as the 90% inhibitory concentration forbacterial growth. A panel of reference compounds were simultaneouslytested for QC approval.

Cytotoxicity Assays

Cytotoxicity of the compounds was evaluated using the MTT assay. HumanHelaM cells grown in 96-well plates were exposed to serial dilutions ofthe tested compounds (final volume of 0.2 ml) and incubated for 72 hoursat 37° C. and 5% CO2 Inhibitors are typically varied over the range of25 to 0.8 μM. The final DMSO concentration in the assay is 0.5%. MTT(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, atetrazole) was added and reduced to purple formazan only in livingcells. Solubilization of the formazan crystals was achieved by adding100 μl 2-propanol. Cell viability was determined by measuring theabsorbance of the reduced formazan, giving a purple color, at 540 nm and690 nm. The absorbance measured at 690 nm was automatically subtractedfrom the absorbance at 540 nm, to eliminate the effects of non-specificabsorption. The percent cytotoxicity achieved by the compounds wascalculated according to standard methods. Cytotoxicity is reported asCC50, the concentration that causes a 50% reduction in cell viability.

Protocol for MIC Determination of Compounds on ECO/PAE/STA inMicroplates

-   -   Add 4-5 colonies of an overnight grown plate to 5 ml Mueller        Hinton medium    -   Incubate for 3-6 hours at 37° C. in shaker incubator (300 rpm)    -   Measure OD at 600 nm (OD600=1->109 CFU/ml)    -   Dilute bacteria until 105 CFU/ml in medium    -   Prepare 2-fold dilutions in microplates in 100 μl Mueller Hinton        medium (final conc. from 64 to 0.125 μg/ml)    -   Add 100 μl of bacteria dilution to each well    -   Incubate for 18-20 hours at 37° C.    -   Check the growth against the control visually        MIC is the lowest concentration with no growth (90% inhibition        of growth)        Biological Results

Compound of the examples/invention are/were tested in the antibacterialsusceptibility and/or the cyctotoxicity assays described above.Compounds of the examples/invention are/were found to exhibit an IC90value of less than 50 μg/mL (e.g. less than 15 μg/mL), a CC50 value ofless than 50 μg/mL (e.g. less than 15 μg/mL) and/or a MIC90 of less than10 μg/mL (e.g. less than 1 μg/mL), in the respective assays. Certaincompounds exhibited an IC90 value of less than 10 μg/mL (e.g. less than1 μg/mL), or a CC50 value of less than 10 μg/mL (e.g. less than 5 μg/mL)and/or a MIC90 value of less than 0.5 μg/mL, in the respective assays.

Certain compounds may be available from commercially-available sources,e.g. CHEMBRIDGE.

TABLE 1 Compounds of formula (I). # STRUCTURE IC90 (μg/ml) CC50 (μg/ml)1

8.5 2

13.73 3

5.59 >4.5 4

12.91 >11.1 5

2.10 6.3 6

1.05 >10.5 7

14.32 8

5.50 >4.4 9

0.97 5.9 10

1.68 9.9 11

5.49 >10.1 12

5.78 >9.7 13

1.71 5.2 14

9.16 >11.0 15

1.49 >10.1 16

6.92 >11.0 17

13.37 >11.1 18

13.03 >10.7 19

5.57 >11.1 20

7.15 8.1 21

0.39 5.9 22

5.16 8.5 23

7.37 4.4 24

1.68 >11.4 25

3.27 >10.8 26

7.51 5.7 27

9.10 7.1 28

5.28 4.7 29

3.45 8.5 30

5.19 8.8 31

7.32 4.2 32

3.27 5.5 33

13.15 7.6 34

6.99 8.7 35

13.3 7.7 36

2.98 >10.5 37

3.04 9.2 38

5.04 >4.0 39

0.76 7.3 40

0.52 7.0 41

8.66 7.7 42

6.75 5.1 43

2.24 6.2 44

2.23 7.0 45

3.49 4.9 46

4.10 4.2 47

1.74 2.1 48

3.16 2.2 49

12.16 >9.7 50

9.61 >4.0 51

13.45 7.8 52

1.28 6.7 53

5.47 7.5 54

1.29 >10.3 55

0.39 6.3 56

1.49 >10.3 57

0.39 7.3 58

0.69 >10.6 59

>26.7 >10.6 60

>26.7 >10.6 61

>25.9 >10.3 62

>25.9 >10.3 63

2.74 >9.4 64

1.46 >10.1 65

0.13 >4.4 66

<0.21 8.8 67

0.81 >11.1 68

6.10 >10.4 69

3.02 >10.3 70

0.64 6.7 71

<0.22 72

25.94

TABLE 2 Compounds of formula (I). MIC90 # STRUCTURE (μg/ml) 73

>64 74

0.125 75

0.5 76

0.125 77

0.25 78

0.125 79

0.125 80

0.125 81

0.125 82

1 83

0.125 84

0.125 85

0.125 86

0.125 87

2 88

0.125 89

0.125 90

0.25 91

0.5 92

0.125 93

0.125

The invention claimed is:
 1. A compound of formula I:

wherein: Y represents:

none or one of N^(v), N^(w), N^(x), N^(y) and N^(z) (preferably one)represent(s) —N° and the others represent —C(H)═; n represents 0 or 1;X¹ represents —N—, X² is —C(H)—, and Q¹ represents a direct bond; R^(z)represents hydrogen or C₁₋₆ alkyl; R^(x) represents C₁₋₆ alkyl(optionally substituted by one or more substituents selected from A¹),aryl or heteroaryl (which latter two groups are each optionallysubstituted by one or more substituents selected from A² and A³,respectively); R^(y), R^(y1) and R^(y2) independently representhydrogen, halo, —CN, —OR¹⁰, —N(R¹¹)(R¹²) or C₁₋₆ alkyl (optionallysubstituted by one or more halo atoms); A¹, A², A³ and A⁴ independentlyrepresent halo, —CN, —OR¹, —S(O)₀₋₂C₁₋₃alkyl, C₁₋₆ alkyl (optionallysubstituted by one or more halo substituents), heterocycloalkyl(optionally substituted by one or more substituents selected from C₁₋₃alkyl and halo), aryl or heteroaryl (which latter two groups areoptionally substituted by one or more substituents selected from B¹ andB², respectively); each R¹ and R¹⁰ independently represent hydrogen,C₁₋₆ alkyl (optionally substituted by one or more halo substituents),aryl or heteroaryl (which latter two groups are optionally substitutedby one or more substituents selected from halo, C₁₋₃ alkyl and —O—C₁₋₃alkyl); R¹¹ and R¹² independently represent hydrogen or C₁₋₆ alkyl; B¹and B² independently represent halo, —CN, C₁₋₆ alkyl (optionallysubstituted by one or more halo, —OH or —O—C₁₋₆ alkyl (optionallysubstituted by one or more halo atoms), or a pharmaceutically acceptablesalt thereof, with the proviso that the compound is not:


2. The compound according to claim 1 wherein: R^(x) represents C₁₋₆alkyl (optionally substituted by one or more substituents selected fromA¹); A⁴ (which is preferably present on a carbon atom of the phenylring, and is preferably in the para-position) represents halo, —CN or—OC₁₋₃ alkyl; A¹ represents halo, —CN, C₁₋₆ alkyl or —OR¹; either all ofR^(y), R^(y1) and R^(y2) represent hydrogen or, more preferably, atleast one of R^(y), R^(y1) and R^(y2) (preferably R^(y)) represents asubstituent other than hydrogen and the others (preferably R^(y1) andR^(y2)) represents hydrogen (i.e. there is preferably one substituentpresent on the phenyl ring, preferably in the meta-position); when R^(y)is other than hydrogen, it preferably represents halo, —OCH₃ or —CN;and/or R¹ represents hydrogen.
 3. The compound according to claim 1wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 4. A combination of (a) acompound as defined in claim 1, and (b) one or more other antibacterialagents.